70 results on '"Zhaoqian Su"'
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2. A multiscale study on the mechanisms of spatial organization in ligand-receptor interactions on cell surfaces
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Zhaoqian Su, Kalyani Dhusia, and Yinghao Wu
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Ligand-receptor oligomerization ,Multiscale simulation ,Biotechnology ,TP248.13-248.65 - Abstract
The binding of cell surface receptors with extracellular ligands triggers distinctive signaling pathways, leading into the corresponding phenotypic variation of cells. It has been found that in many systems, these ligand-receptor complexes can further oligomerize into higher-order structures. This ligand-induced oligomerization of receptors on cell surfaces plays an important role in regulating the functions of cell signaling. The underlying mechanism, however, is not well understood. One typical example is proteins that belong to the tumor necrosis factor receptor (TNFR) superfamily. Using a generic multiscale simulation platform that spans from atomic to subcellular levels, we compared the detailed physical process of ligand-receptor oligomerization for two specific members in the TNFR superfamily: the complex formed between ligand TNFα and receptor TNFR1 versus the complex formed between ligand TNFβ and receptor TNFR2. Interestingly, although these two systems share high similarity on the tertiary and quaternary structural levels, our results indicate that their oligomers are formed with very different dynamic properties and spatial patterns. We demonstrated that the changes of receptor’s conformational fluctuations due to the membrane confinements are closely related to such difference. Consistent to previous experiments, our simulations also showed that TNFR can preassemble into dimers prior to ligand binding, while the introduction of TNF ligands induced higher-order oligomerization due to a multivalent effect. This study, therefore, provides the molecular basis to TNFR oligomerization and reveals new insights to TNFR-mediated signal transduction. Moreover, our multiscale simulation framework serves as a prototype that paves the way to study higher-order assembly of cell surface receptors in many other bio-systems.
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- 2021
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3. A computational model for understanding the oligomerization mechanisms of TNF receptor superfamily
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Zhaoqian Su and Yinghao Wu
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Kinetic Monte-Carlo simulation ,Tumor necrosis factor ,Receptor oligomerization ,Biotechnology ,TP248.13-248.65 - Abstract
By recognizing members in the tumor necrosis factor (TNF) receptor superfamily, TNF ligand proteins function as extracellular cytokines to activate various signaling pathways involved in inflammation, proliferation, and apoptosis. Most ligands in TNF superfamily are trimeric and can simultaneously bind to three receptors on cell surfaces. It has been experimentally observed that the formation of these molecular complexes further triggers the oligomerization of TNF receptors, which in turn regulate the intracellular signaling processes by providing transient compartmentalization in the membrane proximal regions of cytoplasm. In order to decode the molecular mechanisms of oligomerization in TNF receptor superfamily, we developed a new computational method that can physically simulate the spatial-temporal process of binding between TNF ligands and their receptors. The simulations show that the TNF receptors can be organized into hexagonal oligomers. The formation of this spatial pattern is highly dependent not only on the molecular properties such as the affinities of trans and cis binding, but also on the cellular factors such as the concentration of TNF ligands in the extracellular area or the density of TNF receptors on cell surfaces. Moreover, our model suggests that if TNF receptors are pre-organized into dimers before ligand binding, these lateral interactions between receptor monomers can play a positive role in stabilizing the ligand-receptor interactions, as well as in regulating the kinetics of receptor oligomerization. Altogether, this method throws lights on the mechanisms of TNF ligand-receptor interactions in cellular environments.
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- 2020
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4. A computational study of co-inhibitory immune complex assembly at the interface between T cells and antigen presenting cells.
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Zhaoqian Su, Kalyani Dhusia, and Yinghao Wu
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Biology (General) ,QH301-705.5 - Abstract
The activation and differentiation of T-cells are mainly directly by their co-regulatory receptors. T lymphocyte-associated protein-4 (CTLA-4) and programed cell death-1 (PD-1) are two of the most important co-regulatory receptors. Binding of PD-1 and CTLA-4 with their corresponding ligands programed cell death-ligand 1 (PD-L1) and B7 on the antigen presenting cells (APC) activates two central co-inhibitory signaling pathways to suppress T cell functions. Interestingly, recent experiments have identified a new cis-interaction between PD-L1 and B7, suggesting that a crosstalk exists between two co-inhibitory receptors and the two pairs of ligand-receptor complexes can undergo dynamic oligomerization. Inspired by these experimental evidences, we developed a coarse-grained model to characterize the assembling of an immune complex consisting of CLTA-4, B7, PD-L1 and PD-1. These four proteins and their interactions form a small network motif. The temporal dynamics and spatial pattern formation of this network was simulated by a diffusion-reaction algorithm. Our simulation method incorporates the membrane confinement of cell surface proteins and geometric arrangement of different binding interfaces between these proteins. A wide range of binding constants was tested for the interactions involved in the network. Interestingly, we show that the CTLA-4/B7 ligand-receptor complexes can first form linear oligomers, while these oligomers further align together into two-dimensional clusters. Similar phenomenon has also been observed in other systems of cell surface proteins. Our test results further indicate that both co-inhibitory signaling pathways activated by B7 and PD-L1 can be down-regulated by the new cis-interaction between these two ligands, consistent with previous experimental evidences. Finally, the simulations also suggest that the dynamic and the spatial properties of the immune complex assembly are highly determined by the energetics of molecular interactions in the network. Our study, therefore, brings new insights to the co-regulatory mechanisms of T cell activation.
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- 2021
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5. Understanding the Targeting Mechanisms of Multi-Specific Biologics in Immunotherapy with Multiscale Modeling
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Zhaoqian Su, Bo Wang, Steven C. Almo, and Yinghao Wu
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Immunology ,Therapeutics ,Science - Abstract
Summary: Immunotherapeutics are frequently associated with adverse side effects due to the elicitation of global immune modulation. To lower the risk of these side effects, recombinant DNA technology is employed to enhance the selectivity of cell targeting by genetically fusing different biomolecules, yielding new species referred to as multi-specific biologics. The design of new multi-specific biologics is a central challenge for the realization of new immunotherapies. To understand the molecular determinants responsible for regulating the binding between multi-specific biologics and surface-bound membrane receptors, we developed a multiscale computational framework that integrates various simulation approaches covering different timescales and spatial resolutions. Our model system of multi-specific biologics contains two natural ligands of immune receptors, which are covalently tethered by a peptide linker. Using this method, a number of interesting features of multi-specific biologics were identified. Our study therefore provides an important strategy to design the next-generation biologics for immunotherapy.
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- 2020
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6. Cadherin clusters stabilized by a combination of specific and nonspecific cis-interactions
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Connor J Thompson, Zhaoqian Su, Vinh H Vu, Yinghao Wu, Deborah E Leckband, and Daniel K Schwartz
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E-cadherin ,membrane protein ,lateral interactions ,single-molecule ,adherens junctions ,cell adhesion ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
We demonstrate a combined experimental and computational approach for the quantitative characterization of lateral interactions between membrane-associated proteins. In particular, weak, lateral (cis) interactions between E-cadherin extracellular domains tethered to supported lipid bilayers, were studied using a combination of dynamic single-molecule Förster Resonance Energy Transfer (FRET) and kinetic Monte Carlo (kMC) simulations. Cadherins are intercellular adhesion proteins that assemble into clusters at cell-cell contacts through cis- and trans- (adhesive) interactions. A detailed and quantitative understanding of cis-clustering has been hindered by a lack of experimental approaches capable of detecting and quantifying lateral interactions between proteins on membranes. Here single-molecule intermolecular FRET measurements of wild-type E-cadherin and cis-interaction mutants combined with simulations demonstrate that both nonspecific and specific cis-interactions contribute to lateral clustering on lipid bilayers. Moreover, the intermolecular binding and dissociation rate constants are quantitatively and independently determined, demonstrating an approach that is generalizable for other interacting proteins.
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- 2020
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7. Using Coarse-Grained Simulations to Characterize the Mechanisms of Protein–Protein Association
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Kalyani Dhusia, Zhaoqian Su, and Yinghao Wu
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coarse-grained simulations ,protein-protein association ,physics-based force field ,statistical potential ,Microbiology ,QR1-502 - Abstract
The formation of functionally versatile protein complexes underlies almost every biological process. The estimation of how fast these complexes can be formed has broad implications for unravelling the mechanism of biomolecular recognition. This kinetic property is traditionally quantified by association rates, which can be measured through various experimental techniques. To complement these time-consuming and labor-intensive approaches, we developed a coarse-grained simulation approach to study the physical processes of protein–protein association. We systematically calibrated our simulation method against a large-scale benchmark set. By combining a physics-based force field with a statistically-derived potential in the simulation, we found that the association rates of more than 80% of protein complexes can be correctly predicted within one order of magnitude relative to their experimental measurements. We further showed that a mixture of force fields derived from complementary sources was able to describe the process of protein–protein association with mechanistic details. For instance, we show that association of a protein complex contains multiple steps in which proteins continuously search their local binding orientations and form non-native-like intermediates through repeated dissociation and re-association. Moreover, with an ensemble of loosely bound encounter complexes observed around their native conformation, we suggest that the transition states of protein–protein association could be highly diverse on the structural level. Our study also supports the idea in which the association of a protein complex is driven by a “funnel-like” energy landscape. In summary, these results shed light on our understanding of how protein–protein recognition is kinetically modulated, and our coarse-grained simulation approach can serve as a useful addition to the existing experimental approaches that measure protein–protein association rates.
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- 2020
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8. Encoding the space of protein-protein binding interfaces by artificial intelligence.
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Zhaoqian Su, Kalyani Dhusia, and Yinghao Wu
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- 2024
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9. Machine-learning-based structural analysis of interactions between antibodies and antigens.
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Grace Zhang, Xiaohan Kuang, Yuhao Zhang, Yunchao Liu, Zhaoqian Su, Tom Zhang, and Yinghao Wu
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- 2024
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10. From small wrinkles to Schallamach waves during rubber friction: In situ experiment and 3D simulation
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Zhibo, Cui, Zhaoqian, Su, Dandan, Hou, Genzong, Li, Jian, Wu, Benlong, Su, Yuyan, Liu, and Youshan, Wang
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- 2021
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11. Computational Assessment of Protein-protein Binding Affinity by Reversely Engineering the Energetics in Protein Complexes.
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Bo Wang, Zhaoqian Su, and Yinghao Wu
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- 2021
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12. Computational analyses of the interactome between TNF and TNFR superfamilies.
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Kalyani Dhusia, Zhaoqian Su, and Yinghao Wu
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- 2023
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13. Study on site selection for a cruise home port in the Yangtze River Delta region from the perspective of safety
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Zhaoqian Su and Yingjie Xiao
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Ocean Engineering ,Oceanography - Abstract
To improve the safety of cruise tourism in the Yangtze River Delta region (YRD), a new cruise ship home port is needed. This paper studies the process for selection of a site for the new cruise home port. Through analysis of previous cases of cruise tourism safety accidents, it is found that the basic situation of the cruise port, such as the channel, the port, logistics support and scenic places to visit, is important to cruise operation safety. An index system of site selection for a cruise home port is established, and the optimal choice of location for a regional cruise home port – between Shanghai, Zhoushan and Nantong – is analysed by the analytic hierarchy process (AHP). The research shows that the order of preferred site for the cruise home port is Zhoushan, then Shanghai and, third, Nantong. This paper can provide a reference for the layout of the whole industry chain of the cruise economy in the YRD in the future. This will promote the integration of development of the YRD, and enhance the regional connectivity and policy system efficiency in the YRD.
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- 2022
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14. Hot deformation behavior and dynamic recrystallization kinetic modeling of the Mg–7Gd–3Y–1Zn–0.5Zr alloy
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Chen Zhong, Yongjun Li, Qichi Le, Minglong Ma, Xinggang Li, Guoliang Shi, Jiawei Yuan, Zhaoqian Sun, and Kui Zhang
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Mg alloy ,Hot deformation ,Microstructure ,Dynamic recrystallization kinetic modeling ,LPSO phase ,Mining engineering. Metallurgy ,TN1-997 - Abstract
In this study, the microstructure evolution on hot deformation was investigated and a dynamic recrystallization (DRX) kinetic model was constructed based on the hot deformation behavior of the homogenized state Mg–7Gd–3Y–1Zn–0.5Zr (VW73B) alloy within 713–773 K and 0.01–0.1 s−1. The DRX critical strain reduced when the deformation temperature (T) increased and increased when the strain rate (ε˙) increased. The variation trend of the DRX volume fraction was inversely proportional to the critical DRX strain. The constructed DRX kinetic model was modified by introducing a compensation factor; the modified model showed a mean absolute deviation of the DRX volume fraction of 1.8%. Combined with the microstructure analysis, it can be found that the Long Period Stacking Ordered (LPSO) phase is able to promote DRX during the hot deformation, but its ability to promote DRX is less pronounced than that of grain boundaries. At the block-shaped LPSO phase interface, the grain boundary arched by strain induction provided a nucleation site for DRX, enabling discontinuous dynamic recrystallization (DDRX). At the lamellar LPSO phase interface, continuous dynamic recrystallization (CDRX) occurred predominantly through the continuous migration and merging of subgrains, resulting in the formation of DRX grains. The results of this study could guide future research on the DRX of the VW73B alloys with varied applications.
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- 2025
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15. EXCESP: A Structure-Based Online Database for Extracellular Interactome of Cell Surface Proteins in Humans
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Kalyani Dhusia, Carlos Madrid, Zhaoqian Su, and Yinghao Wu
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Systems Biology ,Protein Interaction Mapping ,Computational Biology ,Humans ,Membrane Proteins ,General Chemistry ,Biochemistry ,Signal Transduction - Abstract
The interactions between ectodomains of cell surface proteins are vital players in many important cellular processes, such as regulating immune responses, coordinating cell differentiation, and shaping neural plasticity. However, while the construction of a large-scale protein interactome has been greatly facilitated by the development of high-throughput experimental techniques, little progress has been made to support the discovery of extracellular interactome for cell surface proteins. Harnessed by the recent advances in computational modeling of protein-protein interactions, here we present a structure-based online database for the extracellular interactome of cell surface proteins in humans, called EXCESP. The database contains both experimentally determined and computationally predicted interactions among all type-I transmembrane proteins in humans. All structural models for these interactions and their binding affinities were further computationally modeled. Moreover, information such as expression levels of each protein in different cell types and its relation to various signaling pathways from other online resources has also been integrated into the database. In summary, the database serves as a valuable addition to the existing online resources for the study of cell surface proteins. It can contribute to the understanding of the functions of cell surface proteins in the era of systems biology.
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- 2022
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16. Dissecting the General Mechanisms of Protein Cage Self-assembly by Coarse-grained Simulations
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Zhaoqian Su and Yinghao Wu
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Molecular Biology ,Biochemistry - Abstract
The development of artificial protein cages has recently gained massive attention due to their promising application prospect as novel delivery vehicles for therapeutics. These nanoparticles are formed through a process called self-assembly, in which individual subunits spontaneously arrange into highly ordered patterns via non-covalent but specific interactions. Therefore, the first step towards the design of novel engineered protein cages is to understand the general mechanisms of their self-assembling dynamics. Here we have developed a new computational method to tackle this problem. Our method is based on a coarse-grained model and a diffusion-reaction simulation algorithm. Using a tetrahedral cage as test model, we showed that self-assembly of protein cage requires of a seeding process in which specific configurations of kinetic intermediate states are identified. We further found that there is a critical concentration to trigger self-assembly of protein cages. This critical concentration allows that cages can only be successfully assembled under a persistently high concentration. Additionally, phase diagram of self-assembly has been constructed by systematically testing the model across a wide range of binding parameters. Finally, our simulations demonstrated the importance of protein's structural flexibility in regulating the dynamics of cage assembly. In summary, this study throws lights on the general principles underlying self-assembly of large cage-like protein complexes and thus provides insights to design new nanomaterials. This article is protected by copyright. All rights reserved.
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- 2022
17. Computational Simulation of Holin S105 in Membrane Bilayer and Its Dimerization Through a Helix-Turn-Helix Motif
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Yinghao Wu, Brian Zhou, and Zhaoqian Su
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0303 health sciences ,Physiology ,Chemistry ,030310 physiology ,Bilayer ,Biophysics ,Cell Biology ,Bacteriophage lambda ,Turn (biochemistry) ,Viral Proteins ,03 medical and health sciences ,Transmembrane domain ,Membrane protein ,Holin ,Helix ,Amino Acid Sequence ,Lipid bilayer ,Dimerization ,Alpha helix ,Helix-Turn-Helix Motifs ,030304 developmental biology - Abstract
During the final step of the bacteriophage infection cycle, the cytoplasmic membrane of host cells is disrupted by small membrane proteins called holins. The function of holins in cell lysis is carried out by forming a highly ordered structure called lethal lesion, in which the accumulation of holins in the cytoplasmic membrane leads to the sudden opening of a hole in the middle of this oligomer. Previous studies showed that dimerization of holins is a necessary step to induce their higher order assembly. However, the molecular mechanism underlying the holin-mediated lesion formation is not well understood. In order to elucidate the functions of holin, we first computationally constructed a structural model for our testing system: the holin S105 from bacteriophage lambda. All atom molecular dynamic simulations were further applied to refine its structure and study its dynamics as well as interaction in lipid bilayer. Additional simulations on association between two holins provide supportive evidence to the argument that the C-terminal region of holin plays a critical role in regulating the dimerization. In detail, we found that the adhesion of specific nonpolar residues in transmembrane domain 3 (TMD3) in a polar environment serves as the driven force of dimerization. Our study therefore brings insights to the design of binding interfaces between holins, which can be potentially used to modulate the dynamics of lesion formation.
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- 2021
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18. Characterizing the function of domain linkers in regulating the dynamics of multi‐domain fusion proteins by microsecond molecular dynamics simulations and artificial intelligence
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Yinghao Wu, Zhaoqian Su, and Bo Wang
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Computer science ,Recombinant Fusion Proteins ,Gene Expression ,Molecular Dynamics Simulation ,Protein Engineering ,Biochemistry ,Article ,Domain (software engineering) ,03 medical and health sciences ,Molecular dynamics ,Protein Domains ,Artificial Intelligence ,Structural Biology ,Humans ,Amino Acids ,Pliability ,Cluster analysis ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,business.industry ,Protein dynamics ,030302 biochemistry & molecular biology ,Rational design ,Computational Biology ,Fusion protein ,Hierarchical clustering ,Benchmarking ,Mutagenesis, Insertional ,Artificial intelligence ,business ,Function (biology) - Abstract
Multi-domain proteins are not only formed through natural evolution but can also be generated by recombinant DNA technology. Because many fusion proteins can enhance the selectivity of cell targeting, these artificially produced molecules, called multi-specific biologics, are promising drug candidates, especially for immunotherapy. Moreover, the rational design of domain linkers in fusion proteins is becoming an essential step toward a quantitative understanding of the dynamics in these biopharmaceutics. We developed a computational framework to characterize the impacts of peptide linkers on the dynamics of multi-specific biologics. Specifically, we first constructed a benchmark containing six types of linkers that represent various lengths and degrees of flexibility and used them to connect two natural proteins as a test system. We then projected the microsecond dynamics of these proteins generated from Anton onto a coarse-grained conformational space. We further analyzed the similarity of dynamics among different proteins in this low-dimensional space by a neural-network-based classification model. Finally, we applied hierarchical clustering to place linkers into different subgroups based on the classification results. The clustering results suggest that the length of linkers, which is used to spatially separate different functional modules, plays the most important role in regulating the dynamics of this fusion protein. Given the same number of amino acids, linker flexibility functions as a regulator of protein dynamics. In summary, we illustrated that a new computational strategy can be used to study the dynamics of multi-domain fusion proteins by a combination of long timescale molecular dynamics simulation, coarse-grained feature extraction, and artificial intelligence.
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- 2021
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19. Computational Analyses of the Interactome between TNF and TNFR Superfamilies
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Kalyani Dhusia, Zhaoqian Su, and Yinghao Wu
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Computational Mathematics ,Structural Biology ,Organic Chemistry ,Biochemistry - Abstract
Proteins in the tumor necrosis factor (TNF) superfamily (TNFSF) regulate diverse cellular processes by interacting with their receptors in the TNF receptor (TNFR) superfamily (TNFRSF). Ligands and receptors in these two superfamilies form a complicated network of interactions, in which the same ligand can bind to different receptors and the same receptor can be shared by different ligands. In order to study these interactions on a systematic level, a TNFSF-TNFRSF interactome was constructed in this study by searching the database which consists of both experimentally measured and computationally predicted protein-protein interactions (PPIs). The interactome contains a total number of 194 interactions between 18 TNFSF ligands and 29 TNFRSF receptors in human. We modeled the structure for each ligand-receptor interaction in the network. Their binding affinities were further computationally estimated based on modeled structures. Our computational outputs, which are all publicly accessible, serve as a valuable addition to the currently limited experimental resources to study TNF-mediated cell signaling.
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- 2022
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20. How does the same ligand activate signaling of different receptors in TNFR superfamily: a computational study
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Zhaoqian Su and Yinghao Wu
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Cell Biology ,Molecular Biology ,Biochemistry - Abstract
TNFα is a highly pleiotropic cytokine inducing inflammatory signaling pathways. It is initially presented on plasma membrane of cells (mTNFα), and also exists in a soluble variant (sTNFα) after cleavage. The ligand is shared by two structurally similar receptors, TNFR1 and TNFR2. Interestingly, while sTNFα preferentially stimulates TNFR1, TNFR2 signaling can only be activated by mTNFα. How can two similar receptors respond to the same ligand in such a different way? We employed computational simulations in multiple scales to address this question. We found that both mTNFα and sTNFα can trigger the clustering of TNFR1. The size of clusters induced by sTNFα is constantly larger than the clusters induced by mTNFα. The systems of TNFR2, on the other hand, show very different behaviors. Only when the interactions between TNFR2 are very weak, mTNFα can trigger the receptors to form very large clusters. Given the same weak binding affinity, only small oligomers were obtained in the system of sTNFα. Considering that TNF-mediated signaling is modulated by the ligand-induced clustering of receptors on cell surface, our study provided the mechanistic foundation to the phenomenon that different isoforms of the ligand can lead to highly distinctive signaling patterns for its receptors.
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- 2022
21. Understanding the Impacts of Conformational Dynamics on the Regulation of Protein–Protein Association by a Multiscale Simulation Method
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Zhaoqian Su, Kalyani Dhusia, and Yinghao Wu
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010304 chemical physics ,Protein Conformation ,Chemistry ,Association (object-oriented programming) ,Protein protein ,Dynamics (mechanics) ,Intermolecular force ,Rigid structure ,Proteins ,Molecular Dynamics Simulation ,01 natural sciences ,Measure (mathematics) ,Computer Science Applications ,Kinetics ,0103 physical sciences ,Probability distribution ,Kinetic Monte Carlo ,Physical and Theoretical Chemistry ,Biological system ,Monte Carlo Method ,Algorithms ,Protein Binding - Abstract
Complexes formed among diverse proteins carry out versatile functions in nearly all physiological processes. Association rates which measure how fast proteins form various complexes are of fundamental importance to characterize their functions. The association rates are not only determined by the energetic features at binding interfaces of a protein complex but also influenced by the intrinsic conformational dynamics of each protein in the complex. Unfortunately, how this conformational effect regulates protein association has never been calibrated on a systematic level. To tackle this problem, we developed a multiscale strategy to incorporate the information on protein conformational variations from Langevin dynamic simulations into a kinetic Monte Carlo algorithm of protein-protein association. By systematically testing this approach against a large-scale benchmark set, we found the association of a protein complex with a relatively rigid structure tends to be reduced by its conformational fluctuations. With specific examples, we further show that higher degrees of structural flexibility in various protein complexes can facilitate the searching and formation of intermolecular interactions and thereby accelerate their associations. In general, the integration of conformational dynamics can improve the correlation between experimentally measured association rates and computationally derived association probabilities. Finally, we analyzed the statistical distributions of different secondary structural types on protein-protein binding interfaces and their preference to the change of association rates. Our study, to the best of our knowledge, is the first computational method that systematically estimates the impacts of protein conformational dynamics on protein-protein association. It throws lights on the molecular mechanisms of how protein-protein recognition is kinetically modulated.
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- 2020
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22. Effect of extrusion ratio on microstructures, mechanical properties, and high cycle fatigue behavior of Mg–5Zn–1Mn alloy
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Tong Mu, Jiawei Yuan, Kai Zhang, Yongjun Li, Xinggang Li, Minglong Ma, Guoliang Shi, Zhaoqian Sun, and Kui Zhang
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Mg-5Zn–1Mn alloy ,Extrusion ratio ,High cycle fatigue ,Microstructure evolution ,Twinning/detwinning ,Dislocation slip ,Mining engineering. Metallurgy ,TN1-997 - Abstract
The effects of extrusion ratio (ER) on the microstructures, static mechanical properties, and tension-compression high cycle fatigue (HCF) behavior of the as-extruded Mg–5Zn–1Mn (ZM51) alloy was investigated systematically, and the HCF mechanism was discussed. The results show that texture weakening and grain refinement caused by increasing the ER can effectively enhance the static mechanical properties and alleviate the tensile-compressive asymmetry of the alloy. The fatigue strength at 107 cycles is 124 ± 5, 138 ± 4, and 142 ± 5 MPa for ER8, ER11.5, and ER23, respectively, and the corresponding fatigue ratio is approximately 0.45, 0.49, and 0.50, which means that the as-extruded ZM51 alloy possesses outstanding fatigue resistance. The failure analysis and microstructure evolution of post-fatigued samples demonstrated that the stress amplitudes and microstructure characteristics strongly influence the HCF mechanism of the alloy. At high-stress load, close to the tensile yield strength 160–180 MPa, abundant {101‾2} residual twin bands were observed near the fracture surface. Twinning/detwinning deformation is the dominant fatigue mechanism due to the plastic deformation incompatibility between the matrix and the residual twins. At low-stress load, close to the fatigue strength 125–145 MPa, the fatigue crack initiation mechanism transits from twinning/detwinning to dislocation slip. Grain refinement and texture weakening inhibit the activation of {101‾2} twins, alleviate the twin-dislocation interaction, and promote dislocation slip to dominate the fatigue deformation, thereby enhancing the fatigue life of the alloy. This work provides new insight into the design and development for enhancing the fatigue resistance of wrought Mg alloy to ensure the long-term service safety of structural materials.
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- 2024
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23. Sliding characteristics of bioinspired polydimethylsiloxane micropillars under bending states
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Shouyao Liu, Zhibo Cui, Zhaoqian Su, Bin Zhu, Shixue He, Benlong Su, Jian Wu, and Youshan Wang
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Mechanics of Materials ,Mechanical Engineering ,Surfaces and Interfaces ,Surfaces, Coatings and Films - Published
- 2022
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24. Effects of Sn on the electrochemistry and discharge performances of as-extruded Mg-1.2Ga as an anode for Mg-air batteries
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Zehua Chen, Yongan Zhang, Minglong Ma, Kui Zhang, Yongjun Li, Guoliang Shi, Jiawei Yuan, Zhaoqian Sun, and Gang Zhao
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Mg-air battery ,Mg-Ga-Sn ,Discharge performance ,Dissolution-reprecipitation ,Electrochemical behavior ,Technology - Abstract
The effects of Sn in as-extruded Mg-1.2Ga alloys on the electrochemical and discharge properties were investigated by in-situ electrochemistry, half-cell and air-cell tests to provide new ideas for the development of magnesium alloy anode materials. The addition of Sn promoted grain refinement and deformation precipitation on the extrusion streamlines. Extrusion can effectively reduce the |bc| value of the alloy, improving the cathodic hydrogen control process. After the addition of Sn, more secondary phases are introduced. The redeposition and dissolution of Sn and Ga are enhanced. In conclusion, the GT12 alloy has excellent anode efficiency and average cell voltage, and its maximum discharge capacity (1292.98 mAh·g−1 at 75 mA·cm−2) is 55 mAh·g−1 higher than that of the as-cast alloy, showing great potential for development.
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- 2025
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25. A computational model for understanding the oligomerization mechanisms of TNF receptor superfamily
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Yinghao Wu and Zhaoqian Su
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Tumor necrosis factor ,lcsh:Biotechnology ,Biophysics ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,lcsh:TP248.13-248.65 ,Genetics ,Extracellular ,Receptor ,Kinetic Monte-Carlo simulation ,030304 developmental biology ,ComputingMethodologies_COMPUTERGRAPHICS ,0303 health sciences ,Chemistry ,Compartmentalization (psychology) ,Ligand (biochemistry) ,Computer Science Applications ,Cell biology ,Receptor oligomerization ,Cytoplasm ,030220 oncology & carcinogenesis ,Tumor necrosis factor alpha ,Signal transduction ,030217 neurology & neurosurgery ,Intracellular ,Biotechnology ,Research Article - Abstract
Graphical abstract, By recognizing members in the tumor necrosis factor (TNF) receptor superfamily, TNF ligand proteins function as extracellular cytokines to activate various signaling pathways involved in inflammation, proliferation, and apoptosis. Most ligands in TNF superfamily are trimeric and can simultaneously bind to three receptors on cell surfaces. It has been experimentally observed that the formation of these molecular complexes further triggers the oligomerization of TNF receptors, which in turn regulate the intracellular signaling processes by providing transient compartmentalization in the membrane proximal regions of cytoplasm. In order to decode the molecular mechanisms of oligomerization in TNF receptor superfamily, we developed a new computational method that can physically simulate the spatial-temporal process of binding between TNF ligands and their receptors. The simulations show that the TNF receptors can be organized into hexagonal oligomers. The formation of this spatial pattern is highly dependent not only on the molecular properties such as the affinities of trans and cis binding, but also on the cellular factors such as the concentration of TNF ligands in the extracellular area or the density of TNF receptors on cell surfaces. Moreover, our model suggests that if TNF receptors are pre-organized into dimers before ligand binding, these lateral interactions between receptor monomers can play a positive role in stabilizing the ligand-receptor interactions, as well as in regulating the kinetics of receptor oligomerization. Altogether, this method throws lights on the mechanisms of TNF ligand-receptor interactions in cellular environments.
- Published
- 2020
26. Study on the prediction model of accidents and incidents of cruise ship operation based on machine learning
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Zhaoqian Su, Cuilin Wu, Yingjie Xiao, and Hongdi He
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Environmental Engineering ,Ocean Engineering - Published
- 2022
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27. Methane Clathrate Formation is Catalyzed and Kinetically Inhibited by the Same Molecule: Two Facets of Methanol
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Saman Alavi, Zhaoqian Su, John A. Ripmeester, Cristiano L. Dias, and Gedaliah Wolosh
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Aqueous solution ,010304 chemical physics ,Methane clathrate ,Clathrate hydrate ,Nucleation ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Methane ,alcohols ,0104 chemical sciences ,Surfaces, Coatings and Films ,Hydrophobic effect ,chemistry.chemical_compound ,chemistry ,solvates ,0103 physical sciences ,Materials Chemistry ,molecules ,hydrocarbons ,Methanol ,Physical and Theoretical Chemistry ,Hydrate ,hydrate formation - Abstract
Here, we perform molecular dynamics simulations to provide atomic-level insights into the dual roles of methanol in enhancing and delaying the rate of methane clathrate hydrate nucleation. Consistent with experiments, we find that methanol slows clathrate hydrate nucleation above 250 K but promotes clathrate formation at temperatures below 250 K. We show that this behavior can be rationalized by the unusual temperature dependence of the methane–methanol interaction in an aqueous solution, which emerges due to the hydrophobic effect. In addition to its antifreeze properties at temperatures above 250 K, methanol competes with water to interact with methane prior to the formation of clathrate nuclei. Below 250 K, methanol encourages water to occupy the space between methane molecules favoring clathrate formation and it may additionally promote water mobility.
- Published
- 2021
28. Coarse-grained simulations of phase separation driven by DNA and its sensor protein cGAS
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Yinghao Wu, Zhaoqian Su, and Kalyani Dhusia
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Models, Molecular ,Work (thermodynamics) ,Biophysics ,Biochemistry ,Models, Biological ,Supramolecular assembly ,chemistry.chemical_compound ,Protein Aggregates ,Humans ,Computer Simulation ,Molecular Biology ,chemistry.chemical_classification ,Biomolecule ,Condensation ,Membrane Proteins ,Polymer ,DNA ,Affinities ,Nucleotidyltransferases ,Kinetics ,Order (biology) ,chemistry ,Biological system ,Algorithms ,Signal Transduction - Abstract
The enzyme cGAS functions as a sensor that recognizes the cytosolic DNA from foreign pathogen. The activation of the protein triggers the transcription of inflammatory genes, leading into the establishment of an antipathogen state. An interesting new discovery is that the detection of DNA by cGAS induced the formation of liquid-like droplets. However how cells regulate the formation of these droplets is still not fully understood. In order to unravel the molecular mechanism beneath the DNA-mediated phase separation of cGAS, we developed a polymer-based coarse-grained model which takes into accounts the basic structural organization in DNA and cGAS, as well as the binding properties between these biomolecules. This model was further integrated into a hybrid simulation algorithm. With this computational method, a multi-step kinetic process of aggregation between cGAS and DNA was observed. Moreover, we systematically tested the model under different concentrations and binding parameters. Our simulation results show that phase separation requires both cGAS dimerization and protein-DNA interactions, whereas polymers can be kinetically trapped in small aggregates under strong binding affinities. Additionally, we demonstrated that supramolecular assembly can be facilitated by increasing the number of functional modules in protein or DNA polymers, suggesting that multivalency and intrinsic disordered regions play positive roles in regulating phase separation. This is consistent to previous experimental evidences. Taken together, this is, to the best of our knowledge, the first computational model to study condensation of cGAS-DNA complexes. While the method can reach the timescale beyond the capability of atomic-level MD simulations, it still includes information about spatial arrangement of functional modules in biopolymers that is missing in the mean-field theory. Our work thereby adds a useful dimension to a suite of existing experimental and computational techniques to study the dynamics of phase separation in biological systems.
- Published
- 2021
29. Understanding the impacts of cellular environments on ligand binding of membrane receptors by computational simulations
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Kalyani Dhusia, Zhaoqian Su, and Yinghao Wu
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010304 chemical physics ,Chemistry ,Cell ,Kinetics ,Cell Membrane ,General Physics and Astronomy ,Receptors, Cell Surface ,010402 general chemistry ,Ligands ,01 natural sciences ,0104 chemical sciences ,Membrane ,medicine.anatomical_structure ,Cell surface receptor ,0103 physical sciences ,Extracellular ,medicine ,Biophysics ,Computer Simulation ,Kinetic Monte Carlo ,Physical and Theoretical Chemistry ,Receptor ,Monte Carlo Method ,Function (biology) - Abstract
Binding of cell surface receptors with their extracellular ligands initiates various intracellular signaling pathways. However, our understanding of the cellular functions of these receptors is very limited due to the fact that in vivo binding between ligands and receptors has only been successfully measured in a very small number of cases. In living cells, receptors are anchored on surfaces of the plasma membrane, which undergoes thermal undulations. Moreover, it has been observed in various systems that receptors can be organized into oligomers prior to ligand binding. It is not well understood how these cellular factors play roles in regulating the dynamics of ligand-receptor interactions. Here, we tackled these problems by using a coarse-grained kinetic Monte Carlo simulation method. Using this method, we demonstrated that the membrane undulations cause a negative effect on ligand-receptor interactions. We further found that the preassembly of membrane receptors on the cell surface can not only accelerate the kinetics of ligand binding but also reduce the noises during the process. In general, our study highlights the importance of membrane environments in regulating the function of membrane receptors in cells. The simulation method can be potentially applied to specific receptor systems involved in cell signaling.
- Published
- 2021
30. Author response for 'Characterizing the function of domain linkers in regulating the dynamics of multi‐domain fusion proteins by microsecond molecular dynamics simulations and artificial intelligence'
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Bo Wang, Yinghao Wu, and Zhaoqian Su
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Physics ,Multi domain ,Microsecond ,Molecular dynamics ,Dynamics (mechanics) ,Function (mathematics) ,Biological system ,Fusion protein ,Domain (software engineering) - Published
- 2021
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31. A Multiscale Study on the Mechanisms of Spatial Organization in Ligand-receptor Interactions on Cell Surfaces
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zhaoqian su
- Published
- 2020
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32. A multiscale study on the mechanisms of spatial organization in ligand-receptor interactions on cell surfaces
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Yinghao Wu, Zhaoqian Su, and Kalyani Dhusia
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Cell signaling ,Ligand-receptor oligomerization ,Cell ,Biophysics ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,Cell surface receptor ,Genetics ,Extracellular ,medicine ,Receptor ,030304 developmental biology ,ComputingMethodologies_COMPUTERGRAPHICS ,0303 health sciences ,Chemistry ,Multiscale simulation ,Ligand (biochemistry) ,Phenotype ,Computer Science Applications ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Signal transduction ,TP248.13-248.65 ,Biotechnology ,Research Article - Abstract
Graphical abstract, The binding of cell surface receptors with extracellular ligands triggers distinctive signaling pathways, leading into the corresponding phenotypic variation of cells. It has been found that in many systems, these ligand-receptor complexes can further oligomerize into higher-order structures. This ligand-induced oligomerization of receptors on cell surfaces plays an important role in regulating the functions of cell signaling. The underlying mechanism, however, is not well understood. One typical example is proteins that belong to the tumor necrosis factor receptor (TNFR) superfamily. Using a generic multiscale simulation platform that spans from atomic to subcellular levels, we compared the detailed physical process of ligand-receptor oligomerization for two specific members in the TNFR superfamily: the complex formed between ligand TNFα and receptor TNFR1 versus the complex formed between ligand TNFβ and receptor TNFR2. Interestingly, although these two systems share high similarity on the tertiary and quaternary structural levels, our results indicate that their oligomers are formed with very different dynamic properties and spatial patterns. We demonstrated that the changes of receptor’s conformational fluctuations due to the membrane confinements are closely related to such difference. Consistent to previous experiments, our simulations also showed that TNFR can preassemble into dimers prior to ligand binding, while the introduction of TNF ligands induced higher-order oligomerization due to a multivalent effect. This study, therefore, provides the molecular basis to TNFR oligomerization and reveals new insights to TNFR-mediated signal transduction. Moreover, our multiscale simulation framework serves as a prototype that paves the way to study higher-order assembly of cell surface receptors in many other bio-systems.
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- 2020
33. Mechanistic dissection of spatial organization in NF-κB signaling pathways by hybrid simulations
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Zhaoqian Su, Yinghao Wu, and Kalyani Dhusia
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Scaffold protein ,Chemistry ,Biophysics ,NF-kappa B ,Biochemistry ,Receptor stimulation ,Cell biology ,Nf κb signaling ,Tumor Necrosis Factor Receptor-Associated Factors ,Functional importance ,Molecular mechanism ,Original Article ,Signal transduction ,Tumor necrosis factor receptor ,Transcription factor ,Spatial organization ,Signal Transduction - Abstract
The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is one of the most important transcription factors involved in the regulation of inflammatory signaling pathways. Inappropriate activation of these pathways has been linked to autoimmunity and cancers. Emerging experimental evidences have been showing the existence of elaborate spatial organizations for various molecular components in the pathways. One example is the scaffold protein tumor necrosis factor receptor associated factor (TRAF). While most TRAF proteins form trimeric quaternary structure through their coiled-coil regions, the N-terminal region of some members in the family can further be dimerized. This dimerization of TRAF trimers can drive them into higher-order clusters as a response to receptor stimulation, which functions as a spatial platform to mediate the downstream poly-ubiquitination. However, the molecular mechanism underlying the TRAF protein clustering and its functional impacts are not well-understood. In this article, we developed a hybrid simulation method to tackle this problem. The assembly of TRAF-based signaling platform at the membrane-proximal region is modeled with spatial resolution, while the dynamics of downstream signaling network, including the negative feedbacks through various signaling inhibitors, is simulated as stochastic chemical reactions. These two algorithms are further synchronized under a multiscale simulation framework. Using this computational model, we illustrated that the formation of TRAF signaling platform can trigger an oscillatory NF-κB response. We further demonstrated that the temporal patterns of downstream signal oscillations are closely regulated by the spatial factors of TRAF clustering, such as the geometry and energy of dimerization between TRAF trimers. In general, our study sheds light on the basic mechanism of NF-κB signaling pathway and highlights the functional importance of spatial regulation within the pathway. The simulation framework also showcases its potential of application to other signaling pathways in cells.
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- 2020
34. A computational study of co-inhibitory immune complex assembly at the interface between T cells and antigen presenting cells
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Yinghao Wu, Zhaoqian Su, and Kalyani Dhusia
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0301 basic medicine ,Proteomics ,B7 Antigens ,T-Lymphocytes ,Programmed Cell Death 1 Receptor ,Plasma protein binding ,Antigen-Antibody Complex ,Immune Receptors ,Biochemistry ,B7-H1 Antigen ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Biochemical Simulations ,CTLA-4 Antigen ,Biology (General) ,Receptor ,Materials ,Immune System Proteins ,Ecology ,Chemistry ,T Cells ,Monomers ,Crosstalk (biology) ,medicine.anatomical_structure ,Computational Theory and Mathematics ,030220 oncology & carcinogenesis ,Modeling and Simulation ,Physical Sciences ,Protein Interaction Networks ,Signal transduction ,Cellular Types ,Network Analysis ,Protein Binding ,Research Article ,Signal Transduction ,Computer and Information Sciences ,QH301-705.5 ,T cell ,Immune Cells ,Immunology ,Materials Science ,Antigen-Presenting Cells ,Molecular Dynamics Simulation ,Protein–protein interaction ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Genetics ,medicine ,Humans ,Antigen-presenting cell ,Dimers ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Blood Cells ,T-cell receptor ,Computational Biology ,Biology and Life Sciences ,Proteins ,Cell Biology ,Polymer Chemistry ,T Cell Receptors ,030104 developmental biology ,Oligomers ,Biophysics - Abstract
The activation and differentiation of T-cells are mainly directly by their co-regulatory receptors. T lymphocyte-associated protein-4 (CTLA-4) and programed cell death-1 (PD-1) are two of the most important co-regulatory receptors. Binding of PD-1 and CTLA-4 with their corresponding ligands programed cell death-ligand 1 (PD-L1) and B7 on the antigen presenting cells (APC) activates two central co-inhibitory signaling pathways to suppress T cell functions. Interestingly, recent experiments have identified a new cis-interaction between PD-L1 and B7, suggesting that a crosstalk exists between two co-inhibitory receptors and the two pairs of ligand-receptor complexes can undergo dynamic oligomerization. Inspired by these experimental evidences, we developed a coarse-grained model to characterize the assembling of an immune complex consisting of CLTA-4, B7, PD-L1 and PD-1. These four proteins and their interactions form a small network motif. The temporal dynamics and spatial pattern formation of this network was simulated by a diffusion-reaction algorithm. Our simulation method incorporates the membrane confinement of cell surface proteins and geometric arrangement of different binding interfaces between these proteins. A wide range of binding constants was tested for the interactions involved in the network. Interestingly, we show that the CTLA-4/B7 ligand-receptor complexes can first form linear oligomers, while these oligomers further align together into two-dimensional clusters. Similar phenomenon has also been observed in other systems of cell surface proteins. Our test results further indicate that both co-inhibitory signaling pathways activated by B7 and PD-L1 can be down-regulated by the new cis-interaction between these two ligands, consistent with previous experimental evidences. Finally, the simulations also suggest that the dynamic and the spatial properties of the immune complex assembly are highly determined by the energetics of molecular interactions in the network. Our study, therefore, brings new insights to the co-regulatory mechanisms of T cell activation., Author summary The activation of a T cell can be regulated by the receptors on its surface, such as CTLA-4 and PD-1. People used to think that these two receptors inhibit T cell activation through distinct pathways. However, recent experiments discovered that the ligands of these two receptors, B7 and PD-L1, can interact with each other on the same surface of antigen presenting cells. Here we utilized computational simulations to investigate functional roles of this newly discovered interaction in T cell coregulation. The specific environment of interface between T cell and antigen presenting cell has been taken into account of our model. Ligand and receptors randomly diffuse within this interface area. They further involve in different types of interactions, with each other from the same side or the opposite side of cell surface. Using this method, we found ligands and receptors can not only form complexes, but also aggregate into large-scale clusters. We also demonstrated that the engagement between B7 and PD-L1 can reduce the interactions with their corresponding receptors. This study, therefore, offers new insights to our understanding of signal regulation in T cells.
- Published
- 2020
35. Author response: Cadherin clusters stabilized by a combination of specific and nonspecific cis-interactions
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Vinh H. Vu, Daniel K. Schwartz, Deborah E. Leckband, Zhaoqian Su, Connor J. Thompson, and Yinghao Wu
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Cadherin ,Chemistry ,Cell biology - Published
- 2020
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36. Understand the Functions of Scaffold Proteins in Cell Signaling by a Mesoscopic Simulation Method
- Author
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Zhaoqian Su, Yinghao Wu, and Kalyani Dhusia
- Subjects
Scaffold protein ,0303 health sciences ,Mesoscopic physics ,Cell signaling ,Multiprotein complex ,Chemistry ,Biophysics ,Proteins ,Articles ,Receptor–ligand kinetics ,03 medical and health sciences ,Cytosol ,Kinetics ,0302 clinical medicine ,Thermodynamics ,Computer Simulation ,Signal transduction ,Linker ,030217 neurology & neurosurgery ,030304 developmental biology ,Protein Binding ,Signal Transduction - Abstract
Scaffold proteins are central players in regulating the spatial-temporal organization of many important signaling pathways in cells. They offer physical platforms to downstream signaling proteins so that their transient interactions in a crowded and heterogeneous environment of cytosol can be greatly facilitated. However, most scaffold proteins tend to simultaneously bind more than one signaling molecule, which leads to the spatial assembly of multimeric protein complexes. The kinetics of these protein oligomerizations are difficult to quantify by traditional experimental approaches. To understand the functions of scaffold proteins in cell signaling, we developed a, to our knowledge, new hybrid simulation algorithm in which both spatial organization and binding kinetics of proteins were implemented. We applied this new technique to a simple network system that contains three molecules. One molecule in the network is a scaffold protein, whereas the other two are its binding targets in the downstream signaling pathway. Each of the three molecules in the system contains two binding motifs that can interact with each other and are connected by a flexible linker. By applying the new simulation method to the model, we show that the scaffold proteins will promote not only thermodynamics but also kinetics of cell signaling given the premise that the interaction between the two signaling molecules is transient. Moreover, by changing the flexibility of the linker between two binding motifs, our results suggest that the conformational fluctuations in a scaffold protein play a positive role in recruiting downstream signaling molecules. In summary, this study showcases the capability of computational simulation in understanding the general principles of scaffold protein functions.
- Published
- 2020
37. A Systematic Test of Receptor Binding Kinetics for Ligands in Tumor Necrosis Factor Superfamily by Computational Simulations
- Author
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Yinghao Wu and Zhaoqian Su
- Subjects
0301 basic medicine ,030103 biophysics ,Protein Conformation ,Cellular differentiation ,tumor necrosis factor superfamily ,computational simulations ,Ligands ,Catalysis ,Article ,Receptors, Tumor Necrosis Factor ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,Cell surface receptor ,binding kinetics ,Humans ,Computer Simulation ,Physical and Theoretical Chemistry ,Decoy receptors ,Receptor ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,Tissue homeostasis ,Chemistry ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,General Medicine ,Ligand (biochemistry) ,Receptor–ligand kinetics ,3. Good health ,Computer Science Applications ,Cell biology ,Kinetics ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Signal transduction ,Protein Binding ,Signal Transduction - Abstract
Ligands in the tumor necrosis factor (TNF) superfamily are one major class of cytokines that bind to their corresponding receptors in the tumor necrosis factor receptor (TNFR) superfamily and initiate multiple intracellular signaling pathways during inflammation, tissue homeostasis, and cell differentiation. Mutations in the genes that encode TNF ligands or TNFR receptors result in a large variety of diseases. The development of therapeutic treatment for these diseases can be greatly benefitted from the knowledge on binding properties of these ligand&ndash, receptor interactions. In order to complement the limitations in the current experimental methods that measure the binding constants of TNF/TNFR interactions, we developed a new simulation strategy to computationally estimate the association and dissociation between a ligand and its receptor. We systematically tested this strategy to a comprehensive dataset that contained structures of diverse complexes between TNF ligands and their corresponding receptors in the TNFR superfamily. We demonstrated that the binding stabilities inferred from our simulation results were compatible with existing experimental data. We further compared the binding kinetics of different TNF/TNFR systems, and explored their potential functional implication. We suggest that the transient binding between ligands and cell surface receptors leads into a dynamic nature of cross-membrane signal transduction, whereas the slow but strong binding of these ligands to the soluble decoy receptors is naturally designed to fulfill their functions as inhibitors of signal activation. Therefore, our computational approach serves as a useful addition to current experimental techniques for the quantitatively comparison of interactions across different members in the TNF and TNFR superfamily. It also provides a mechanistic understanding to the functions of TNF-associated cell signaling pathways.
- Published
- 2020
38. A Multiscale and Comparative Model for Receptor Binding of 2019 Novel Coronavirus and the Implication of its Life Cycle in Host Cells
- Author
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Wu Y and Zhaoqian Su
- Subjects
0303 health sciences ,Innate immune system ,Host (biology) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,fungi ,Biology ,medicine.disease_cause ,Virology ,Article ,Virus ,3. Good health ,Incubation period ,03 medical and health sciences ,0302 clinical medicine ,medicine ,skin and connective tissue diseases ,Receptor ,030217 neurology & neurosurgery ,Function (biology) ,030304 developmental biology ,Coronavirus - Abstract
The respiratory syndrome caused by a new type of coronavirus has been emerging from China and caused more than one million death globally since December 2019. This new virus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the same receptor called Angiotensin-converting enzyme 2 (ACE2) to attack humans as the coronavirus that caused the severe acute respiratory syndrome (SARS) seventeen years ago. Both viruses recognize ACE2 through the spike proteins (S-protein) on their surfaces. It was found that the S-protein from the SARS coronavirus (SARS-CoV) bind stronger to ACE2 than SARS-CoV-2. However, function of a bio-system is often under kinetic, rather than thermodynamic, control. To address this issue, we constructed a structural model for complex formed between ACE2 and the S-protein from SARS-CoV-2, so that the rate of their association can be estimated and compared with the binding of S-protein from SARS-CoV by a multiscale simulation method. Our simulation results suggest that the association of new virus to the receptor is slower than SARS, which is consistent with the experimental data obtained very recently. We further integrated this difference of association rate between virus and receptor into a mathematical model which describes the life cycle of virus in host cells and its interplay with the innate immune system. Interestingly, we found that the slower association between virus and receptor can result in longer incubation period, while still maintaining a relatively higher level of viral concentration in human body. Our computational study therefore provides, from the molecular level, one possible explanation that this new pandemic by far spread much faster than SARS.
- Published
- 2020
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39. Molecular interactions accounting for protein denaturation by urea
- Author
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Cristiano L. Dias and Zhaoqian Su
- Subjects
Aqueous solution ,010304 chemical physics ,010402 general chemistry ,Condensed Matter Physics ,01 natural sciences ,Small molecule ,Atomic and Molecular Physics, and Optics ,0104 chemical sciences ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,Molecular dynamics ,symbols.namesake ,Monomer ,chemistry ,Computational chemistry ,0103 physical sciences ,Materials Chemistry ,Urea ,symbols ,Side chain ,Organic chemistry ,Physical and Theoretical Chemistry ,Potential of mean force ,van der Waals force ,Spectroscopy - Abstract
Urea destabilizes proteins when added to aqueous solutions. To study its molecular mechanism we perform explicit all-atom molecular dynamics simulations of unrestrained poly-glycine, poly-alanine, and poly-leucine monomers as well as of extended poly-alanine and poly-leucine dimers. We show that poly-leucine monomers become less compact when urea is added to water whereas poly-glycine and poly-alanine monomers are only weakly affected by this co-solvent. Consistent with these results, we find that only the potential of mean force (PMF) of extended poly-leucine dimers changes significantly when urea is added to water. To rationalize these observations, we perform detail analysis of extended dimers. Urea is found to occupy positions between leucine's side chains that are not accessible to water. This allows extra van der Waals interactions between urea and side-chains to be formed which favor the monomeric state. In contrast, urea-solvent interactions are found to favor the dimeric state. The sum of these two energetic terms, i.e., urea-peptide and urea-solvent, provides the enthalpic driving force for urea denaturation. We show here that this enthalpy correlates with the potential of mean force of poly-leucine dimers. Moreover, the framework developed here is general and may be used to provide insights into effects of other small molecules on protein interactions.
- Published
- 2017
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40. EXCESP: A Structure-Based Online Database for Extracellular Interactome of Cell Surface Proteins in Humans.
- Author
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Dhusia, Kalyani, Madrid, Carlos, Zhaoqian Su, and Yinghao Wu
- Published
- 2022
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41. Multiscale Simulation Unravel the Kinetic Mechanisms of Inflammasome Assembly
- Author
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Zhaoqian Su and Yinghao Wu
- Subjects
Inflammasomes ,Computational biology ,Molecular Dynamics Simulation ,Article ,Domain (software engineering) ,Protein filament ,03 medical and health sciences ,0302 clinical medicine ,Molecular recognition ,Protein sequencing ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Death domain ,0303 health sciences ,Innate immune system ,Binding Sites ,Chemistry ,Cryoelectron Microscopy ,Inflammasome ,Cell Biology ,Multiscale modeling ,CARD Signaling Adaptor Proteins ,Kinetics ,Monte Carlo Method ,030217 neurology & neurosurgery ,Algorithms ,medicine.drug - Abstract
In the innate immune system, the host defense from the invasion of external pathogens triggers the inflammatory responses. Proteins involved in the inflammatory pathways were often found to aggregate into supramolecular oligomers, called ‘inflammasome’, mostly through the homotypic interaction between their domains that belong to the death domain superfamily. Although much has been known about the formation of these helical molecular machineries, the detailed correlation between the dynamics of their assembly and the structure of each domain is still not well understood. Using the filament formed by the PYD domains of adaptor molecule ASC as a test system, we constructed a new multiscale simulation framework to study the kinetics of inflammasome assembly. We found that the filament assembly is a multi-step, but highly cooperative process. Moreover, there are three types of binding interfaces between domain subunits in the ASC(PYD) filament. The multiscale simulation results suggest that dynamics of domain assembly are rooted in the primary protein sequence which defines the energetics of molecular recognition through three binding interfaces. Interface I plays a more regulatory role than the other two in mediating both the kinetics and the thermodynamics of assembly. Finally, the efficiency of our computational framework allows us to design mutants on a systematic scale and predict their impacts on filament assembly. In summary, this is, to the best of our knowledge, the first simulation method to model the spatial-temporal process of inflammasome assembly. Our work is a useful addition to a suite of existing experimental techniques to study the functions of inflammasome in innate immune system.
- Published
- 2019
42. Computational simulations of TNF receptor oligomerization on plasma membrane
- Author
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Yinghao Wu and Zhaoqian Su
- Subjects
Protein Conformation, alpha-Helical ,Lipid Bilayers ,Plasma protein binding ,Molecular Dynamics Simulation ,Biochemistry ,Article ,03 medical and health sciences ,Molecular dynamics ,Protein structure ,Structural Biology ,Extracellular ,Humans ,Protein Interaction Domains and Motifs ,Binding site ,Receptor ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Chemistry ,Tumor Necrosis Factor-alpha ,030302 biochemistry & molecular biology ,Cell Membrane ,Ligand (biochemistry) ,Kinetics ,Receptors, Tumor Necrosis Factor, Type I ,Biophysics ,Thermodynamics ,Protein Conformation, beta-Strand ,Signal transduction ,Protein Multimerization ,Protein Binding - Abstract
The interactions between tumor necrosis factors (TNFs) and their corresponding receptors (TNFRs) play a pivotal role in inflammatory responses. Upon ligand binding, TNFR receptors were found to form oligomers on cell surfaces. However, the underlying mechanism of oligomerization is not fully understood. In order to tackle this problem, molecular dynamics (MD) simulations have been applied to the complex between TNF receptor-1 (TNFR1) and its ligand TNF-α as a specific test system. The simulations on both all-atom (AA) and coarse-grained (CG) levels achieved the similar results that the extracellular domains of TNFR1 can undergo large fluctuations on plasma membrane, while the dynamics of TNFα-TNFR1 complex is much more constrained. Using the CG model with the Martini force field, we are able to simulate the systems that contain multiple TNFα-TNFR1 complexes with the timescale of micro-seconds. We found that complexes can aggregate into oligomers on the plasma membrane through the lateral interactions between receptors at the end of the CG simulations. We suggest that this spatial organization is essential to the efficiency of signal transduction for ligands that belong to the TNF superfamily. We further show that the aggregation of two complexes is initiated by the association between the N-terminal domains of TNFR1 receptors. Interestingly, the cis-interfaces between N-terminal regions of two TNF receptors have been observed in the previous X-ray crystallographic experiment. Therefore, we provide supportive evidence that cis-interface is of functional importance in triggering the receptor oligomerization. Taken together, our study brings insights to understand the molecular mechanism of TNF signaling.
- Published
- 2019
43. Thermodynamic Stability of Polar and Nonpolar Amyloid Fibrils
- Author
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Jennifer M. Urban, Zhaoqian Su, Farbod Mahmoudinobar, Cristiano L. Dias, and Bradley L. Nilsson
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Quantitative Biology::Biomolecules ,Amyloid ,Materials science ,010304 chemical physics ,Temperature ,Amyloid fibril ,01 natural sciences ,Proof of Concept Study ,Computer Science Applications ,Chemical physics ,0103 physical sciences ,Polar ,Thermodynamics ,Chemical stability ,Amino Acid Sequence ,Physical and Theoretical Chemistry - Abstract
Thermodynamic stabilities of amyloid fibrils remain mostly unknown due to experimental challenges. Here, we combine enhanced sampling methods to simulate all-atom models in explicit water in order to study the stability of nonpolar (Aβ
- Published
- 2019
44. Research on Child-Friendly Evaluation and Optimization Strategies for Rural Public Spaces
- Author
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Jia Fan, Bohong Zheng, Junyou Liu, Fangzhou Tian, and Zhaoqian Sun
- Subjects
child-friendly ,public spaces ,rural ,evaluation system ,analytic hierarchy process (AHP) ,optimization strategies ,Building construction ,TH1-9745 - Abstract
Public spaces are essential for the implementation of child-friendly principles and the development of child-friendly cities, with positive and healthy environments playing a crucial role in supporting children’s well-being and development. However, existing research on child-friendly public spaces predominantly targets economically developed urban areas with robust public service infrastructure, often neglecting rural areas with less advanced facilities. This study utilizes grounded theory and qualitative analysis to propose a child-friendly public space evaluation framework specifically for rural settings. The framework includes four primary indicators—safety, accessibility, comfort, and multifunctionality—and 19 secondary indicators, such as facility safety and plant safety. An empirical investigation was conducted in Baishoupu Town, a child-friendly pilot area within Changsha, China, which is designated as a United Nations Child-Friendly City, and the study encompassed an analysis of 11 rural villages within this area. The findings reveal that while Baishoupu Town demonstrates a relatively high level of child-friendly development, there is significant disparity among individual villages. Key determinants affecting the child-friendliness of rural public spaces include the type of rural industry, per capita income levels, and the degree of policy support. Specifically, the advancement of public service infrastructure and the tourism sector significantly influence the primary indicators. Moreover, while rural road infrastructure is positively correlated with accessibility, the presence of through traffic adversely affects safety indicators. Based on these insights, this study recommends enhancing child-friendliness in rural public spaces through strategic village planning, spatial design improvements, and ensuring child participation. This research provides valuable insights for government policy development and implementation and offers a replicable framework for child-friendly public space development in rural areas globally.
- Published
- 2024
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45. Computational studies of protein-protein dissociation by statistical potential and coarse-grained simulations: a case study on interactions between colicin E9 endonuclease and immunity proteins
- Author
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Yinghao Wu and Zhaoqian Su
- Subjects
Protein Conformation ,Static Electricity ,General Physics and Astronomy ,Colicins ,02 engineering and technology ,Plasma protein binding ,010402 general chemistry ,01 natural sciences ,Molecular Docking Simulation ,Dissociation (chemistry) ,Article ,Protein structure ,Escherichia coli ,Physical and Theoretical Chemistry ,Binding site ,Binding selectivity ,Binding Sites ,Endodeoxyribonucleases ,Chemistry ,Escherichia coli Proteins ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Colicin ,Biophysics ,0210 nano-technology ,Carrier Proteins ,Statistical potential ,Hydrophobic and Hydrophilic Interactions ,Protein Binding - Abstract
Proteins carry out their diverse functions in cells by forming interactions with each other. The dynamics of these interactions are quantified by the measurement of association and dissociation rate constants. Relative to the efforts made to model the association of biomolecules, little has been studied to understand the principles of protein complex dissociation. Using the interaction between colicin E9 endonucleases and immunity proteins as a test system, here we develop a coarse-grained simulation method to explore the dissociation mechanisms of protein complexes. The interactions between proteins in the complex are described by the knowledge-based potential that was constructed by the statistics from available protein complexes in the structural database. Our study provides the supportive evidences to the dual recognition mechanism for the specificity of binding between E9 DNase and immunity proteins, in which the conserved residues of helix III of Im2 and Im9 proteins act as the anchor for binding, while the sequence variations in helix II make positive or negative contributions to specificity. Beyond that, we further suggest that this binding specificity is rooted in the process of complex dissociation instead of association. While we increased the flexibility of protein complexes, we further found that they are less prone to dissociation, suggesting that conformational fluctuations of protein complexes play important functional roles in regulating their binding and dissociation. Our studies therefore bring new insights to the molecule mechanisms of protein-protein interactions, while the method can serve as a new addition to a suite of existing computational tools for the simulations of protein complexes.
- Published
- 2019
46. Computational Assessment of Protein-protein Binding Affinity by Reversely Engineering the Energetics in Protein Complexes
- Author
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Zhaoqian Su, Bo Wang, and Yinghao Wu
- Subjects
0303 health sciences ,Chemistry ,Accurate estimation ,Protein protein ,Energetics ,Cellular functions ,A protein ,Proteins ,Biochemistry ,Protein–protein interaction ,03 medical and health sciences ,Computational Mathematics ,0302 clinical medicine ,Molecular recognition ,Genetics ,Molecular mechanism ,Biophysics ,Molecular Biology ,030217 neurology & neurosurgery ,030304 developmental biology ,Protein Binding - Abstract
The cellular functions of proteins are maintained by forming diverse complexes. The stability of these complexes is quantified by the measurement of binding affinity, while mutations that alter the binding affinity can cause various diseases such as cancer and diabetes. As a result, the accurate estimation of binding stability and the effects of mutations on changes of binding affinity is a crucial step to understanding the biological functions of proteins and their dysfunctional consequences. Based on the hypothesis that the stability of protein complexes is dependent on both the pairwise interactions of residues at its binding interface and all other remaining residues that do not appear at the binding interface, here we computationally reconstruct the binding affinity by decomposing it into the contribution of interfacial residues and the energetic component of other non-interface residues in a protein complex. We further assume that the contributions of both interfacial and non-interfacial residues to the binding affinity depend on their local structural environments such as solvent-accessible surfaces and secondary structural types. The weights of all corresponding parameters are optimized by Monte-Carlo simulations. After cross-validation against a large-scale dataset, we showed that the model not only shows a strong correlation between the absolute values of the experimental and calculated binding affinity but can also be an effective approach to predicting the relative changes of binding affinity from mutations. Moreover, we have found that the optimized weights of many parameters can capture the first-principle chemical and physical features of molecular recognition, therefore reversely engineering the energetics of protein complexes. These results suggest that our method can serve as a useful addition to current computational approaches for predicting binding affinity and understanding the molecular mechanism of protein-protein interactions.
- Published
- 2018
47. Effects of Trimethylamine- N-oxide (TMAO) on Hydrophobic and Charged Interactions
- Author
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Gopal Ravindhran, Zhaoqian Su, and Cristiano L. Dias
- Subjects
Enthalpy ,Trimethylamine N-oxide ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Hydrophobic effect ,chemistry.chemical_compound ,Molecular dynamics ,Methylamines ,Chlorides ,Pentanes ,0103 physical sciences ,Materials Chemistry ,Physical and Theoretical Chemistry ,Potential of mean force ,Physics::Biological Physics ,Quantitative Biology::Biomolecules ,010304 chemical physics ,Sodium ,Water ,0104 chemical sciences ,Surfaces, Coatings and Films ,Neopentane ,chemistry ,Chemical physics ,Thermodynamics ,Umbrella sampling ,Peptides ,Dimerization ,Hydrophobic and Hydrophilic Interactions ,Protein Binding - Abstract
Effects of trimethylamine-N-oxide (TMAO) on hydrophobic and charge–charge interactions are investigated using molecular dynamics simulations. Recently, these interactions in model peptides and in the Trp-Cage miniprotein have been reported to be strongly affected by TMAO. Neopentane dimers and Na+Cl– are used, here, as models for hydrophobic and charge–charge interactions, respectively. Distance-dependent interactions, i.e., potential of mean force, are computed using an umbrella sampling protocol at different temperatures which allows us to determine enthalpy and entropic energies. We find that the large favorable entropic energy and the unfavorable enthalpy, which are characteristic of hydrophobic interactions, become smaller when TMAO is added to water. These changes account for a negligible effect and a stabilizing effect on the strength of hydrophobic interactions for simulations performed with Kast and Netz models of TMAO, respectively. Effects of TMAO on the enthalpy are mainly due to changes in te...
- Published
- 2018
48. Thermodynamics of Aβ16-21dissociation from a fibril: Enthalpy, entropy, and volumetric properties
- Author
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Farbod Mahmoudinobar, Cristiano L. Dias, Srinivasa Rao Jampani, and Zhaoqian Su
- Subjects
Hydrophobic effect ,Molecular dynamics ,Structural Biology ,Chemistry ,Electric potential energy ,Enthalpy ,Thermodynamics ,Umbrella sampling ,Molecular Biology ,Biochemistry ,Heat capacity ,Thermal expansion ,Accessible surface area - Abstract
Here, we provide insights into the thermodynamic properties of A β16-21 dissociation from an amyloid fibril using all-atom molecular dynamics simulations in explicit water. An umbrella sampling protocol is used to compute potentials of mean force (PMF) as a function of the distance ξ between centers-of-mass of the A β16-21 peptide and the preformed fibril at nine temperatures. Changes in the enthalpy and the entropic energy are determined from the temperature dependence of these PMF(s) and the average volume of the simulation box is computed as a function of ξ. We find that the PMF at 310 K is dominated by enthalpy while the entropic energy does not change significantly during dissociation. The volume of the system decreases during dissociation. Moreover, the magnitude of this volume change also decreases with increasing temperature. By defining dock and lock states using the solvent accessible surface area (SASA), we find that the behavior of the electrostatic energy is different in these two states. It increases (unfavorable) and decreases (favorable) during dissociation in lock and dock states, respectively, while the energy due to Lennard-Jones interactions increases continuously in these states. Our simulations also highlight the importance of hydrophobic interactions in accounting for the stability of A β16-21.
- Published
- 2015
- Full Text
- View/download PDF
49. Effects of Trimethylamine- N -oxide on the Conformation of Peptides and its Implications for Proteins
- Author
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Zhaoqian Su, Cristiano L. Dias, and Farbod Mahmoudinobar
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Molecular Conformation ,Proteins ,General Physics and Astronomy ,Trimethylamine N-oxide ,Peptide ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Molecular conformation ,0104 chemical sciences ,Methylamines ,03 medical and health sciences ,chemistry.chemical_compound ,Molecular dynamics ,030104 developmental biology ,Protein structure ,chemistry ,Biophysics ,Peptides ,Hydrophobic and Hydrophilic Interactions - Abstract
To provide insights into the stabilizing mechanisms of trimethylamine-N-oxide (TMAO) on protein structures, we perform all-atom molecular dynamics simulations of peptides and the Trp-cage miniprotein. The effects of TMAO on the backbone and charged residues of peptides are found to stabilize compact conformations, whereas effects of TMAO on nonpolar residues lead to peptide swelling. This suggests competing mechanisms of TMAO on proteins, which accounts for hydrophobic swelling, backbone collapse, and stabilization of charge-charge interactions. These mechanisms are observed in Trp cage.
- Published
- 2017
- Full Text
- View/download PDF
50. Steady state minority carrier lifetime and defect level occupation in thin film CdTe solar cells
- Author
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Zimeng Cheng, Ken K. Chin, Zhaoqian Su, and Alan E. Delahoy
- Subjects
Electron mobility ,genetic structures ,business.industry ,Chemistry ,Band gap ,Low level injection ,Doping ,Metals and Alloys ,Surfaces and Interfaces ,Carrier lifetime ,Cadmium telluride photovoltaics ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Condensed Matter::Materials Science ,Semiconductor ,Depletion region ,Materials Chemistry ,Optoelectronics ,Atomic physics ,business - Abstract
A model consisting of Shockley Read Hall (SRH) recombination under steady state conditions of constant photon injection is proposed in this work to study the steady state minority carrier lifetime in CdS/CdTe thin film solar cells. The SRH recombination rate versus optical injection level is analytically approximated in the junction and neutral regions. In the neutral region, it is found that the recombination rate through certain defect levels has one constant value under lower optical injection conditions and another constant value under higher optical injection conditions with the transition occurring at a critical optical injection level. By simultaneously solving the equations of charge neutrality, charge conservation and SRH recombination in the neutral region, it is found that the compensation of doping and the reduction of minority carrier lifetime by donors in the p-type semiconductor can each be remedied by optical injection. It is also demonstrated that this optical-dependent SRH recombination is significant in large bandgap thin films. The measured minority carrier diffusion length in a CdS/CdTe solar cells, as determined from the steady-state photo-generated carrier collection efficiency, shows the predicted transition of minority carrier lifetime versus optical injection level. A numerical fitting of the indirectly-measured minority carrier lifetime by assuming the minority carrier mobility gives a non-intuitive picture of the p–n junction with a low free hole concentration but a narrow depletion region width.
- Published
- 2014
- Full Text
- View/download PDF
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