222 results on '"Lemmin, Thomas"'
Search Results
2. Structural insights into the mechanism and dynamics of proteorhodopsin biogenesis and retinal scavenging
- Author
-
Hirschi, Stephan, Lemmin, Thomas, Ayoub, Nooraldeen, Kalbermatter, David, Pellegata, Daniele, Ucurum, Zöhre, Gertsch, Jürg, and Fotiadis, Dimitrios
- Published
- 2024
- Full Text
- View/download PDF
3. Atomic insights into the signaling landscape of E. coli PhoQ histidine kinase from molecular dynamics simulations
- Author
-
Lazaridi, Symela, Yuan, Jing, and Lemmin, Thomas
- Published
- 2024
- Full Text
- View/download PDF
4. Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization
- Author
-
Glögl, Matthias, Friedrich, Nikolas, Cerutti, Gabriele, Lemmin, Thomas, Kwon, Young D., Gorman, Jason, Maliqi, Liridona, Mittl, Peer R. E., Hesselman, Maria C., Schmidt, Daniel, Weber, Jacqueline, Foulkes, Caio, Dingens, Adam S., Bylund, Tatsiana, Olia, Adam S., Verardi, Raffaello, Reinberg, Thomas, Baumann, Nicolas S., Rusert, Peter, Dreier, Birgit, Shapiro, Lawrence, Kwong, Peter D., Plückthun, Andreas, and Trkola, Alexandra
- Published
- 2023
- Full Text
- View/download PDF
5. Compressive Sensing Using Iterative Hard Thresholding with Low Precision Data Representation: Theory and Applications
- Author
-
Gürel, Nezihe Merve, Kara, Kaan, Stojanov, Alen, Smith, Tyler, Lemmin, Thomas, Alistarh, Dan, Püschel, Markus, and Zhang, Ce
- Subjects
Statistics - Machine Learning ,Computer Science - Machine Learning - Abstract
Modern scientific instruments produce vast amounts of data, which can overwhelm the processing ability of computer systems. Lossy compression of data is an intriguing solution, but comes with its own drawbacks, such as potential signal loss, and the need for careful optimization of the compression ratio. In this work, we focus on a setting where this problem is especially acute: compressive sensing frameworks for interferometry and medical imaging. We ask the following question: can the precision of the data representation be lowered for all inputs, with recovery guarantees and practical performance? Our first contribution is a theoretical analysis of the normalized Iterative Hard Thresholding (IHT) algorithm when all input data, meaning both the measurement matrix and the observation vector are quantized aggressively. We present a variant of low precision normalized {IHT} that, under mild conditions, can still provide recovery guarantees. The second contribution is the application of our quantization framework to radio astronomy and magnetic resonance imaging. We show that lowering the precision of the data can significantly accelerate image recovery. We evaluate our approach on telescope data and samples of brain images using CPU and FPGA implementations achieving up to a 9x speed-up with negligible loss of recovery quality., Comment: 19 pages, 5 figures, 1 table, in IEEE Transactions on Signal Processing Vol. 68, No. 7, pp. 4268-4282, 2020
- Published
- 2018
- Full Text
- View/download PDF
6. Structure of the human heterodimeric transporter 4F2hc-LAT2 in complex with Anticalin, an alternative binding protein for applications in single-particle cryo-EM
- Author
-
Jeckelmann, Jean-Marc, Lemmin, Thomas, Schlapschy, Martin, Skerra, Arne, and Fotiadis, Dimitrios
- Published
- 2022
- Full Text
- View/download PDF
7. Structure and mechanism of a phosphotransferase system glucose transporter.
- Author
-
Roth, Patrick, Jeckelmann, Jean-Marc, Fender, Inken, Ucurum, Zöhre, Lemmin, Thomas, and Fotiadis, Dimitrios
- Subjects
MOLECULAR structure ,GLUCOSE transporters ,ESCHERICHIA coli ,MOLECULAR dynamics ,CELL membranes - Abstract
Glucose is the primary source of energy for many organisms and is efficiently taken up by bacteria through a dedicated transport system that exhibits high specificity. In Escherichia coli, the glucose-specific transporter IICB
Glc serves as the major glucose transporter and functions as a component of the phosphoenolpyruvate-dependent phosphotransferase system. Here, we report cryo-electron microscopy (cryo-EM) structures of the glucose-bound IICBGlc protein. The dimeric transporter embedded in lipid nanodiscs was captured in the occluded, inward- and occluded, outward-facing conformations. Together with biochemical and biophysical analyses, and molecular dynamics (MD) simulations, we provide insights into the molecular basis and dynamics for substrate recognition and binding, including the gates regulating the binding sites and their accessibility. By combination of these findings, we present a mechanism for glucose transport across the plasma membrane. Overall, this work provides molecular insights into the structure, dynamics, and mechanism of the IICBGlc transporter in a native-like lipid environment. Glucose is a key energy source for many organisms, efficiently transported in bacteria by specific systems. Here, the authors reveal cryo-EM structures of the glucose transporter IICB from E. coli, providing insights into its mechanism and dynamics. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
8. Structure and Function of the Transmembrane Domain of NsaS, an Antibiotic Sensing Histidine Kinase in Staphylococcus aureus
- Author
-
Bhate, Manasi P, Lemmin, Thomas, Kuenze, Georg, Mensa, Bruk, Ganguly, Soumya, Peters, Jason M, Schmidt, Nathan, Pelton, Jeffrey G, Gross, Carol A, Meiler, Jens, and DeGrado, William F
- Subjects
Infectious Diseases ,Emerging Infectious Diseases ,Anti-Bacterial Agents ,Bacitracin ,Bacterial Proteins ,Gene Knockout Techniques ,Histidine Kinase ,Hydrophobic and Hydrophilic Interactions ,Magnetic Resonance Spectroscopy ,Membrane Proteins ,Microbial Sensitivity Tests ,Molecular Dynamics Simulation ,Nisin ,Protein Conformation ,alpha-Helical ,Protein Domains ,Staphylococcus aureus ,Chemical Sciences ,General Chemistry - Abstract
NsaS is one of four intramembrane histidine kinases (HKs) in Staphylococcus aureus that mediate the pathogen's response to membrane active antimicrobials and human innate immunity. We describe the first integrative structural study of NsaS using a combination of solution state NMR spectroscopy, chemical-cross-linking, molecular modeling and dynamics. Three key structural features emerge: First, NsaS has a short N-terminal amphiphilic helix that anchors its transmembrane (TM) bundle into the inner leaflet of the membrane such that it might sense neighboring proteins or membrane deformations. Second, the transmembrane domain of NsaS is a 4-helix bundle with significant dynamics and structural deformations at the membrane interface. Third, the intracellular linker connecting the TM domain to the cytoplasmic catalytic domains of NsaS is a marginally stable helical dimer, with one state likely to be a coiled-coil. Data from chemical shifts, heteronuclear NOE, H/D exchange measurements and molecular modeling suggest that this linker might adopt different conformations during antibiotic induced signaling.
- Published
- 2018
9. Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease.
- Author
-
Condello, Carlo, Lemmin, Thomas, Stöhr, Jan, Nick, Mimi, Wu, Yibing, Maxwell, Alison M, Watts, Joel C, Caro, Christoffer D, Oehler, Abby, Keene, C Dirk, Bird, Thomas D, van Duinen, Sjoerd G, Lannfelt, Lars, Ingelsson, Martin, Graff, Caroline, Giles, Kurt, DeGrado, William F, and Prusiner, Stanley B
- Subjects
Animals ,Mice ,Transgenic ,Alzheimer Disease ,Protein Conformation ,Protein Folding ,Point Mutation ,Amyloid beta-Peptides ,Alzheimer’s disease ,amyloid-β ,conformational strains ,protein misfolding ,spectral imaging ,Alzheimer's disease ,amyloid-beta ,Mice ,Transgenic ,Dementia ,Neurosciences ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias ,Neurodegenerative ,Aging ,Acquired Cognitive Impairment ,Alzheimer's Disease ,2.1 Biological and endogenous factors ,Neurological - Abstract
Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aβ deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT Aβ, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aβ40 fibrils into transgenic mice expressing only WT Aβ induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aβ40 prions induce a conformation of WT Aβ similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aβ prion conformations, which kinetically dominate the spread of prions in the brain.
- Published
- 2018
10. XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction
- Author
-
Thomaston, Jessica L, Woldeyes, Rahel A, Nakane, Takanori, Yamashita, Ayumi, Tanaka, Tomoyuki, Koiwai, Kotaro, Brewster, Aaron S, Barad, Benjamin A, Chen, Yujie, Lemmin, Thomas, Uervirojnangkoorn, Monarin, Arima, Toshi, Kobayashi, Jun, Masuda, Tetsuya, Suzuki, Mamoru, Sugahara, Michihiro, Sauter, Nicholas K, Tanaka, Rie, Nureki, Osamu, Tono, Kensuke, Joti, Yasumasa, Nango, Eriko, Iwata, So, Yumoto, Fumiaki, Fraser, James S, and DeGrado, William F
- Subjects
Chemical Sciences ,Physical Chemistry ,Emerging Infectious Diseases ,Infectious Diseases ,Influenza ,Pneumonia & Influenza ,Amino Acid Motifs ,Hydrogen Bonding ,Ion Channel Gating ,Molecular Dynamics Simulation ,Protein Domains ,Protons ,Static Electricity ,Temperature ,Viral Matrix Proteins ,XFEL ,proton channel ,influenza ,membrane protein - Abstract
The M2 proton channel of influenza A is a drug target that is essential for the reproduction of the flu virus. It is also a model system for the study of selective, unidirectional proton transport across a membrane. Ordered water molecules arranged in "wires" inside the channel pore have been proposed to play a role in both the conduction of protons to the four gating His37 residues and the stabilization of multiple positive charges within the channel. To visualize the solvent in the pore of the channel at room temperature while minimizing the effects of radiation damage, data were collected to a resolution of 1.4 Å using an X-ray free-electron laser (XFEL) at three different pH conditions: pH 5.5, pH 6.5, and pH 8.0. Data were collected on the Inwardopen state, which is an intermediate that accumulates at high protonation of the His37 tetrad. At pH 5.5, a continuous hydrogen-bonded network of water molecules spans the vertical length of the channel, consistent with a Grotthuss mechanism model for proton transport to the His37 tetrad. This ordered solvent at pH 5.5 could act to stabilize the positive charges that build up on the gating His37 tetrad during the proton conduction cycle. The number of ordered pore waters decreases at pH 6.5 and 8.0, where the Inwardopen state is less stable. These studies provide a graphical view of the response of water to a change in charge within a restricted channel environment.
- Published
- 2017
11. De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy.
- Author
-
Polizzi, Nicholas F, Wu, Yibing, Lemmin, Thomas, Maxwell, Alison M, Zhang, Shao-Qing, Rawson, Jeff, Beratan, David N, Therien, Michael J, and DeGrado, William F
- Subjects
Porphyrins ,Proteins ,Ligands ,Temperature ,Models ,Molecular ,Generic health relevance ,Chemical Sciences ,Organic Chemistry - Abstract
Protein catalysis requires the atomic-level orchestration of side chains, substrates and cofactors, and yet the ability to design a small-molecule-binding protein entirely from first principles with a precisely predetermined structure has not been demonstrated. Here we report the design of a novel protein, PS1, that binds a highly electron-deficient non-natural porphyrin at temperatures up to 100 °C. The high-resolution structure of holo-PS1 is in sub-Å agreement with the design. The structure of apo-PS1 retains the remote core packing of the holoprotein, with a flexible binding region that is predisposed to ligand binding with the desired geometry. Our results illustrate the unification of core packing and binding-site definition as a central principle of ligand-binding protein design.
- Published
- 2017
12. Atomic insights into the signaling landscape of E. coli PhoQ Histidine Kinase from Molecular Dynamics simulations
- Author
-
Lazaridi, Symela, primary, Yuan, Jing, additional, and Lemmin, Thomas, additional
- Published
- 2024
- Full Text
- View/download PDF
13. TemBERTure: Advancing protein thermostability prediction with Deep Learning and attention mechanisms
- Author
-
Rodella, Chiara, primary, Lazaridi, Symela, additional, and Lemmin, Thomas, additional
- Published
- 2024
- Full Text
- View/download PDF
14. Dissecting AlphaFold’s Capabilities with Limited Sequence Information
- Author
-
Gut, Jannik Adrian, primary and Lemmin, Thomas, additional
- Published
- 2024
- Full Text
- View/download PDF
15. De novo design of covalently constrained mesosize protein scaffolds with unique tertiary structures
- Author
-
Dang, Bobo, Wu, Haifan, Mulligan, Vikram Khipple, Mravic, Marco, Wu, Yibing, Lemmin, Thomas, Ford, Alexander, Silva, Daniel-Adriano, Baker, David, and DeGrado, William F
- Subjects
Bioengineering ,Generic health relevance ,Amino Acid Sequence ,Coronavirus ,Crystallography ,X-Ray ,Humans ,Models ,Molecular ,Protein Engineering ,Protein Folding ,Protein Structure ,Secondary ,Sequence Homology ,Viral Core Proteins ,covalent core ,protein design ,mesosize protein ,chemical protein synthesis ,computational design - Abstract
The folding of natural proteins typically relies on hydrophobic packing, metal binding, or disulfide bond formation in the protein core. Alternatively, a 3D structure can be defined by incorporating a multivalent cross-linking agent, and this approach has been successfully developed for the selection of bicyclic peptides from large random-sequence libraries. By contrast, there is no general method for the de novo computational design of multicross-linked proteins with predictable and well-defined folds, including ones not found in nature. Here we use Rosetta and Tertiary Motifs (TERMs) to design small proteins that fold around multivalent cross-linkers. The hydrophobic cross-linkers stabilize the fold by macrocyclic restraints, and they also form an integral part of a small apolar core. The designed CovCore proteins were prepared by chemical synthesis, and their structures were determined by solution NMR or X-ray crystallography. These mesosized proteins, lying between conventional proteins and small peptides, are easily accessible either through biosynthetic precursors or chemical synthesis. The unique tertiary structures and ease of synthesis of CovCore proteins indicate that they should provide versatile templates for developing inhibitors of protein-protein interactions.
- Published
- 2017
16. A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells
- Author
-
Stöhr, Jan, Wu, Haifan, Nick, Mimi, Wu, Yibing, Bhate, Manasi, Condello, Carlo, Johnson, Noah, Rodgers, Jeffrey, Lemmin, Thomas, Acharya, Srabasti, Becker, Julia, Robinson, Kathleen, Kelly, Mark JS, Gai, Feng, Stubbs, Gerald, Prusiner, Stanley B, and DeGrado, William F
- Subjects
Chemical Sciences ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Neurosciences ,Acquired Cognitive Impairment ,Dementia ,Alzheimer's Disease ,Aging ,Neurological ,Binding Sites ,Cells ,HEK293 Cells ,Humans ,Microtubules ,Peptide Fragments ,Protein Aggregates ,Protein Aggregation ,Pathological ,tau Proteins ,Organic Chemistry ,Chemical sciences - Abstract
The self-propagation of misfolded conformations of tau underlies neurodegenerative diseases, including Alzheimer's. There is considerable interest in discovering the minimal sequence and active conformational nucleus that defines this self-propagating event. The microtubule-binding region, spanning residues 244-372, reproduces much of the aggregation behaviour of tau in cells and animal models. Further dissection of the amyloid-forming region to a hexapeptide from the third microtubule-binding repeat resulted in a peptide that rapidly forms fibrils in vitro. We show that this peptide lacks the ability to seed aggregation of tau244-372 in cells. However, as the hexapeptide is gradually extended to 31 residues, the peptides aggregate more slowly and gain potent activity to induce aggregation of tau244-372 in cells. X-ray fibre diffraction, hydrogen-deuterium exchange and solid-state NMR studies map the beta-forming region to a 25-residue sequence. Thus, the nucleus for self-propagating aggregation of tau244-372 in cells is packaged in a remarkably small peptide.
- Published
- 2017
17. Infrared and fluorescence assessment of the hydration status of the tryptophan gate in the influenza A M2 proton channel
- Author
-
Markiewicz, Beatrice N, Lemmin, Thomas, Zhang, Wenkai, Ahmed, Ismail A, Jo, Hyunil, Fiorin, Giacomo, Troxler, Thomas, DeGrado, William F, and Gai, Feng
- Subjects
Infectious Diseases ,Pneumonia & Influenza ,Influenza ,Aetiology ,2.2 Factors relating to the physical environment ,Infection ,Chemical Physics - Abstract
The M2 proton channel of the influenza A virus has been the subject of extensive studies because of its critical role in viral replication. As such, we now know a great deal about its mechanism of action, especially how it selects and conducts protons in an asymmetric fashion. The conductance of this channel is tuned to conduct protons at a relatively low biologically useful rate, which allows acidification of the viral interior of a virus entrapped within an endosome, but not so great as to cause toxicity to the infected host cell prior to packaging of the virus. The dynamic, structural and chemical features that give rise to this tuning are not fully understood. Herein, we use a tryptophan (Trp) analog, 5-cyanotryptophan, and various methods, including linear and nonlinear infrared spectroscopies, static and time-resolved fluorescence techniques, and molecular dynamics simulations, to site-specifically interrogate the structure and hydration dynamics of the Trp41 gate in the transmembrane domain of the M2 proton channel. Our results suggest that the Trp41 sidechain adopts the t90 rotamer, the χ2 dihedral angle of which undergoes an increase of approximately 35° upon changing the pH from 7.4 to 5.0. Furthermore, we find that Trp41 is situated in an environment lacking bulk-like water, and somewhat surprisingly, the water density and dynamics do not show a measurable difference between the high (7.4) and low (5.0) pH states. Since previous studies have shown that upon channel opening water flows into the cavity above the histidine tetrad (His37), the present finding thus provides evidence indicating that the lack of sufficient water molecules near Trp41 needed to establish a continuous hydrogen bonding network poses an additional energetic bottleneck for proton conduction.
- Published
- 2016
18. Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study.
- Author
-
Elkins, Matthew R, Wang, Tuo, Nick, Mimi, Jo, Hyunil, Lemmin, Thomas, Prusiner, Stanley B, DeGrado, William F, Stöhr, Jan, and Hong, Mei
- Subjects
Humans ,Guanidine ,Thiazoles ,Peptides ,Magnetic Resonance Spectroscopy ,Temperature ,Binding Sites ,Protein Conformation ,Kinetics ,Phenotype ,Mutation ,Hydrogen-Ion Concentration ,Benzothiazoles ,Amyloid beta-Peptides ,General Chemistry ,Chemical Sciences - Abstract
The amyloid-β (Aβ) peptide of Alzheimer's disease (AD) forms polymorphic fibrils on the micrometer and molecular scales. Various fibril growth conditions have been identified to cause polymorphism, but the intrinsic amino acid sequence basis for this polymorphism has been unclear. Several single-site mutations in the center of the Aβ sequence cause different disease phenotypes and fibrillization properties. The E22G (Arctic) mutant is found in familial AD and forms protofibrils more rapidly than wild-type Aβ. Here, we use solid-state NMR spectroscopy to investigate the structure, dynamics, hydration and morphology of Arctic E22G Aβ40 fibrils. (13)C, (15)N-labeled synthetic E22G Aβ40 peptides are studied and compared with wild-type and Osaka E22Δ Aβ40 fibrils. Under the same fibrillization conditions, Arctic Aβ40 exhibits a high degree of polymorphism, showing at least four sets of NMR chemical shifts for various residues, while the Osaka and wild-type Aβ40 fibrils show a single or a predominant set of chemical shifts. Thus, structural polymorphism is intrinsic to the Arctic E22G Aβ40 sequence. Chemical shifts and inter-residue contacts obtained from 2D correlation spectra indicate that one of the major Arctic conformers has surprisingly high structural similarity with wild-type Aβ42. (13)C-(1)H dipolar order parameters, (1)H rotating-frame spin-lattice relaxation times and water-to-protein spin diffusion experiments reveal substantial differences in the dynamics and hydration of Arctic, Osaka and wild-type Aβ40 fibrils. Together, these results strongly suggest that electrostatic interactions in the center of the Aβ peptide sequence play a crucial role in the three-dimensional fold of the fibrils, and by inference, fibril-induced neuronal toxicity and AD pathogenesis.
- Published
- 2016
19. Designed metalloprotein stabilizes a semiquinone radical.
- Author
-
Ulas, Gözde, Lemmin, Thomas, Gassner, George, Degrado, William, and Wu, Yibing
- Subjects
Amino Acid Sequence ,Benzoquinones ,Magnetic Resonance Spectroscopy ,Metalloproteins ,Models ,Theoretical ,Molecular Dynamics Simulation ,Molecular Sequence Data - Abstract
Enzymes use binding energy to stabilize their substrates in high-energy states that are otherwise inaccessible at ambient temperature. Here we show that a de novo designed Zn(II) metalloprotein stabilizes a chemically reactive organic radical that is otherwise unstable in aqueous media. The protein binds tightly to and stabilizes the radical semiquinone form of 3,5-di-tert-butylcatechol. Solution NMR spectroscopy in conjunction with molecular dynamics simulations show that the substrate binds in the active site pocket where it is stabilized by metal-ligand interactions as well as by burial of its hydrophobic groups. Spectrochemical redox titrations show that the protein stabilized the semiquinone by reducing the electrochemical midpoint potential for its formation via the one-electron oxidation of the catechol by approximately 400 mV (9 kcal mol(-1)). Therefore, the inherent chemical properties of the radical were changed drastically by harnessing its binding energy to the metalloprotein. This model sets the basis for designed enzymes with radical cofactors to tackle challenging chemistry.
- Published
- 2016
20. Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization
- Author
-
Friedrich, Nikolas, Stiegeler, Emanuel, Glögl, Matthias, Lemmin, Thomas, Hansen, Simon, Kadelka, Claus, Wu, Yufan, Ernst, Patrick, Maliqi, Liridona, Foulkes, Caio, Morin, Mylène, Eroglu, Mustafa, Liechti, Thomas, Ivan, Branislav, Reinberg, Thomas, Schaefer, Jonas V., Karakus, Umut, Ursprung, Stephan, Mann, Axel, Rusert, Peter, Kouyos, Roger D., Robinson, John A., Günthard, Huldrych F., Plückthun, Andreas, and Trkola, Alexandra
- Published
- 2021
- Full Text
- View/download PDF
21. High-resolution structure of the amino acid transporter AdiC reveals insights into the role of water molecules and networks in oligomerization and substrate binding
- Author
-
Ilgü, Hüseyin, Jeckelmann, Jean-Marc, Kalbermatter, David, Ucurum, Zöhre, Lemmin, Thomas, and Fotiadis, Dimitrios
- Published
- 2021
- Full Text
- View/download PDF
22. Cryo-EM structure and dynamics of the green-light absorbing proteorhodopsin
- Author
-
Hirschi, Stephan, Kalbermatter, David, Ucurum, Zöhre, Lemmin, Thomas, and Fotiadis, Dimitrios
- Published
- 2021
- Full Text
- View/download PDF
23. The inhibitory mechanism of a small protein reveals its role in antimicrobial peptide sensing
- Author
-
Jiang, Shan, primary, Steup, Lydia C., additional, Kippnich, Charlotte, additional, Lazaridi, Symela, additional, Malengo, Gabriele, additional, Lemmin, Thomas, additional, and Yuan, Jing, additional
- Published
- 2023
- Full Text
- View/download PDF
24. Assembly of the transmembrane domain of E. coli PhoQ histidine kinase: implications for signal transduction from molecular simulations.
- Author
-
Lemmin, Thomas, Soto, Cinque, Clinthorne, Graham, Dal Peraro, Matteo, and Degrado, William
- Subjects
Escherichia coli ,Histidine Kinase ,Membrane Proteins ,Models ,Molecular ,Molecular Dynamics Simulation ,Protein Kinases ,Signal Transduction - Abstract
The PhoQP two-component system is a signaling complex essential for bacterial virulence and cationic antimicrobial peptide resistance. PhoQ is the histidine kinase chemoreceptor of this tandem machine and assembles in a homodimer conformation spanning the bacterial inner membrane. Currently, a full understanding of the PhoQ signal transduction is hindered by the lack of a complete atomistic structure. In this study, an atomistic model of the key transmembrane (TM) domain is assembled by using molecular simulations, guided by experimental cross-linking data. The formation of a polar pocket involving Asn202 in the lumen of the tetrameric TM bundle is crucial for the assembly and solvation of the domain. Moreover, a concerted displacement of the TM helices at the periplasmic side is found to modulate a rotation at the cytoplasmic end, supporting the transduction of the chemical signal through a combination of scissoring and rotational movement of the TM helices.
- Published
- 2013
25. Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1
- Author
-
Xu, Kai, Acharya, Priyamvada, Kong, Rui, Cheng, Cheng, Chuang, Gwo-Yu, Liu, Kevin, Louder, Mark K., O’Dell, Sijy, Rawi, Reda, Sastry, Mallika, Shen, Chen-Hsiang, Zhang, Baoshan, Zhou, Tongqing, Asokan, Mangaiarkarasi, Bailer, Robert T., Chambers, Michael, Chen, Xuejun, Choi, Chang W., Dandey, Venkata P., Doria-Rose, Nicole A., Druz, Aliaksandr, Eng, Edward T., Farney, S. Katie, Foulds, Kathryn E., Geng, Hui, Georgiev, Ivelin S., Gorman, Jason, Hill, Kurt R., Jafari, Alexander J., Kwon, Young D., Lai, Yen-Ting, Lemmin, Thomas, McKee, Krisha, Ohr, Tiffany Y., Ou, Li, Peng, Dongjun, Rowshan, Ariana P., Sheng, Zizhang, Todd, John-Paul, Tsybovsky, Yaroslav, Viox, Elise G., Wang, Yiran, Wei, Hui, Yang, Yongping, Zhou, Amy F., Chen, Rui, Yang, Lu, Scorpio, Diana G., McDermott, Adrian B., Shapiro, Lawrence, Carragher, Bridget, Potter, Clinton S., Mascola, John R., and Kwong, Peter D.
- Published
- 2018
- Full Text
- View/download PDF
26. Structure and supramolecular organization of the canine distemper virus attachment glycoprotein
- Author
-
Kalbermatter, David, Jeckelmann, Jean-Marc, Wyss, Marianne, Shrestha, Neeta, Pliatsika, Dimanthi, Riedl, Rainer, Lemmin, Thomas, Plattet, Philippe, Fotiadis, Dimitrios, Kalbermatter, David, Jeckelmann, Jean-Marc, Wyss, Marianne, Shrestha, Neeta, Pliatsika, Dimanthi, Riedl, Rainer, Lemmin, Thomas, Plattet, Philippe, and Fotiadis, Dimitrios
- Abstract
Canine distemper virus (CDV) is an enveloped RNA morbillivirus that triggers respiratory, enteric, and high incidence of severe neurological disorders. CDV induces devastating outbreaks in wild and endangered animals as well as in domestic dogs in countries associated with suboptimal vaccination programs. The receptor-binding tetrameric attachment (H)-protein is part of the morbilliviral cell entry machinery. Here, we present the cryo-electron microscopy (cryo-EM) structure and supramolecular organization of the tetrameric CDV H-protein ectodomain. The structure reveals that the morbilliviral H-protein is composed of three main domains: stalk, neck, and heads. The most unexpected feature was the inherent asymmetric architecture of the CDV H-tetramer being shaped by the neck, which folds into an almost 90° bent conformation with respect to the stalk. Consequently, two non-contacting receptor-binding H-head dimers, which are also tilted toward each other, are located on one side of an intertwined four helical bundle stalk domain. Positioning of the four protomer polypeptide chains within the neck domain is guided by a glycine residue (G158), which forms a hinge point exclusively in two protomer polypeptide chains. Molecular dynamics simulations validated the stability of the asymmetric structure under near physiological conditions and molecular docking showed that two receptor-binding sites are fully accessible. Thus, this spatial organization of the CDV H-tetramer would allow for concomitant protein interactions with the stalk and head domains without steric clashes. In summary, the structure of the CDV H-protein ectodomain provides new insights into the morbilliviral cell entry system and offers a blueprint for next-generation structure-based antiviral drug discovery.
- Published
- 2023
27. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody
- Author
-
Kong, Rui, Xu, Kai, Zhou, Tongqing, Acharya, Priyamvada, Lemmin, Thomas, Liu, Kevin, Ozorowski, Gabriel, Soto, Cinque, Taft, Justin D., Bailer, Robert T., Cale, Evan M., Chen, Lei, Choi, Chang W., Chuang, Gwo-Yu, Doria-Rose, Nicole A., Druz, Aliaksandr, Georgiev, Ivelin S., Gorman, Jason, Huang, Jinghe, Joyce, M. Gordon, Louder, Mark K., Ma, Xiaochu, McKee, Krisha, O'Dell, Sijy, Pancera, Marie, Yang, Yongping, Blanchard, Scott C., Mothes, Walther, Burton, Dennis R., Koff, Wayne C., Connors, Mark, Ward, Andrew B., Kwong, Peter D., and Mascola, John R.
- Published
- 2016
28. Glycosylator: a Python framework for the rapid modeling of glycans
- Author
-
Lemmin, Thomas and Soto, Cinque
- Published
- 2019
- Full Text
- View/download PDF
29. The inhibitory mechanism of a small protein reveals its role in antimicrobial peptide sensing.
- Author
-
Shan Jiang, Steup, Lydia C., Kippnich, Charlotte, Lazaridi, Symela, Malengo, Gabriele, Lemmin, Thomas, and Jing Yuan
- Subjects
ANTIMICROBIAL peptides ,MEMBRANE proteins ,CATALYTIC domains ,PROTEINS ,DRUG resistance - Abstract
A large number of small membrane proteins have been uncovered in bacteria, but their mechanism of action has remained mostly elusive. Here, we investigate the mechanism of a physiologically important small protein, MgrB, which represses the activity of the sensor kinase PhoQ and is widely distributed among enterobacteria. The PhoQ/PhoP two-component system is a master regulator of the bacterial virulence program and interacts with MgrB to modulate bacterial virulence, fitness, and drug resistance. A combination of cross-linking approaches with functional assays and protein dynamic simulations revealed structural rearrangements due to interactions between MgrB and PhoQ near the membrane/periplasm interface and along the transmembrane helices. These interactions induce the movement of the PhoQ catalytic domain and the repression of its activity. Without MgrB, PhoQ appears to be much less sensitive to antimicrobial peptides, including the commonly used C18G. In the presence of MgrB, C18G promotes MgrB to dissociate from PhoQ, thus activating PhoQ via derepression. Our findings reveal the inhibitory mechanism of the small protein MgrB and uncover its importance in antimicrobial peptide sensing. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
30. Structure and supramolecular organization of the canine distemper virus attachment glycoprotein
- Author
-
Kalbermatter, David, primary, Jeckelmann, Jean-Marc, additional, Wyss, Marianne, additional, Shrestha, Neeta, additional, Pliatsika, Dimanthi, additional, Riedl, Rainer, additional, Lemmin, Thomas, additional, Plattet, Philippe, additional, and Fotiadis, Dimitrios, additional
- Published
- 2023
- Full Text
- View/download PDF
31. The inhibitory mechanism of a small protein reveals its role in antimicrobial peptide sensing
- Author
-
Jiang, Shan, primary, Steup, Lydia C., additional, Kippnich, Charlotte, additional, Lazaridi, Symela, additional, Malengo, Gabriele, additional, Lemmin, Thomas, additional, and Yuan, Jing, additional
- Published
- 2022
- Full Text
- View/download PDF
32. "Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2"
- Author
-
Vestergaard, Anna L., Coleman, Jonathan A., Lemmin, Thomas, Mikkelsen, Stine A., Molday, Laurie L., Vilsen, Bente, Molday, Robert S., Peraro, Matteo Dal, and Andersen, Jens Peter
- Published
- 2014
33. Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1
- Author
-
Kwong, Peter D., Chuang, Gwo‐Yu, DeKosky, Brandon J., Gindin, Tatyana, Georgiev, Ivelin S., Lemmin, Thomas, Schramm, Chaim A., Sheng, Zizhang, Soto, Cinque, Yang, An‐Suei, Mascola, John R., and Shapiro, Lawrence
- Published
- 2017
- Full Text
- View/download PDF
34. Allosteric mechanism of signal transduction in the two-component system histidine kinase PhoQ
- Author
-
Mensa, Bruk, primary, Polizzi, Nicholas F, additional, Molnar, Kathleen S, additional, Natale, Andrew M, additional, Lemmin, Thomas, additional, and DeGrado, William F, additional
- Published
- 2021
- Full Text
- View/download PDF
35. Author response: Allosteric mechanism of signal transduction in the two-component system histidine kinase PhoQ
- Author
-
Mensa, Bruk, primary, Polizzi, Nicholas F, additional, Molnar, Kathleen S, additional, Natale, Andrew M, additional, Lemmin, Thomas, additional, and DeGrado, William F, additional
- Published
- 2021
- Full Text
- View/download PDF
36. A coiled coil switch mediates cold sensing by the thermosensory protein DesK
- Author
-
Saita, Emilio, Abriata, Luciano A., Tsai, Yi Ting, Trajtenberg, Felipe, Lemmin, Thomas, Buschiazzo, Alejandro, Dal Peraro, Matteo, de Mendoza, Diego, and Albanesi, Daniela
- Published
- 2015
- Full Text
- View/download PDF
37. Ease. ML: A Lifecycle Management System for Machine Learning
- Author
-
Aguilar Melgar, Leonel, Dao, David, Gan, Shaoduo, Gürel, Nezihe M., Hollenstein, Nora, Jiang, Jiawei, Karlaš, Bojan, Lemmin, Thomas, Li, Tian, Li, Yang, Rao, Susie Xi, Rausch, Johannes, Renggli, Cedric, Rimanic, Luka, Weber, Maurice, Zhang, Shuai, Zhao, Zhikuan, Schawinski, Kevin, Wu, Wentao, and Zhang, Ce
- Subjects
020204 information systems ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,02 engineering and technology ,010303 astronomy & astrophysics ,01 natural sciences - Abstract
We present Ease.ML, a lifecycle management system for machine learning (ML). Unlike many existing works, which focus on improving individual steps during the lifecycle of ML application development, Ease.ML focuses on managing and automating the entire lifecycle itself. We present user scenarios that have motivated the development of Ease.ML, the eight-step Ease.ML process that covers the lifecycle of ML application development; the foundation of Ease.ML in terms of a probabilistic database model and its connection to information theory; and our lessons learned, which hopefully can inspire future research., Proceedings of the Annual Conference on Innovative Data Systems Research (CIDR), 2021
- Published
- 2021
- Full Text
- View/download PDF
38. Additional file 1 of High-resolution structure of the amino acid transporter AdiC reveals insights into the role of water molecules and networks in oligomerization and substrate binding
- Author
-
Ilgü, Hüseyin, Jeckelmann, Jean-Marc, Kalbermatter, David, Ucurum, Zöhre, Lemmin, Thomas, and Fotiadis, Dimitrios
- Abstract
Additional file 1: Supplementary Figures and Tables. Fig. S1. Schematic representation of the alternating access mechanism. The major conformational changes and states of the transporter are shown, which are necessary to allow alternating substrate access from either side of the membrane to the substrate-binding site. Transporter, substrate and lipid molecules are colored in blue, orange and light brown, respectively. The different conformational states shown are a: outward-open, substrate-free; b: outward-open, substrate-bound; c: outward-facing, substrate occluded; d: substrate-bound, fully occluded; e: inward-facing, substrate occluded; f: inward-open, substrate-bound; g: inward-open, substrate-free; h: substrate-free, fully occluded. Fig. S2. Quality of the electron density of AdiC. All TMs are displayed as viewed from the membrane plane and boxed into TM-groups belonging to inverted repeats (left) and the dimerization interface (right). Starting and ending amino acid residues of corresponding TMs are labeled. The TMs are displayed as sticks (cyan) and the corresponding 2Fo-Fc electron density map is contoured at 1.0 σ and shown as blue colored mesh. Fig. S3. Structural details of AdiC. (A) TM1 and TM6 are discontinuous and their loop regions connecting the α-helical segments are in close proximity and involved in substrate-binding. TM1 and TM6 are represented as light blue ribbons and the side chains as lines. The α-helical segments of TM1 (TM1a and TM1b) and TM6 (TM6a and TM6b) are highlighted as cylinders and labeled accordingly. The respective N- and C-terminal residues of these segments are labeled as well. (B) The largest interface contribution for AdiC homodimer formation is the interaction between TM11 and TM12. TM12 of monomer A (blue) and TM11 of monomer B (yellow) are displayed as ribbons. Interdigitating, non-polar amino acid residues involved in dimer formation are shown as sticks and labeled. Fig. S4. Comparison of the number of water molecules found in the substrate-binding sites of AdiC structures solved at different resolutions. (A) In the 2.2 Å AdiC structure [16], seven water molecules could be found in the substrate-binding sites of each monomer. (B) In the 1.7 Å AdiC structure of the present study, twenty-one and fifteen water molecules were detected in monomers A and B, respectively. The substrate-binding site cavity was defined as the solvent accessible volume between the indole nitrogen atom of W293 and the side chain oxygen atom of the S26 (borders are indicated with dashed lines and respective amino acids are shown as gray sticks). The two AdiC monomers are represented as ribbons and are colored in blue and yellow color hues. Water molecules are displayed as red spheres. Fig. S5. Water induced linkage of TM domains. (A-D) Interactions of water molecules (orange) with amino acid main chains (blue sticks) and side chains (cyan sticks). Respective interactions between atoms are shown with dashed lines (distances are given in Å). The corresponding 2Fo-Fc electron density map of the interaction regions is contoured at 1.0 σ and is displayed with a light blue mesh representation. Involved TMs are indicated, and amino acids are labeled in the one letter code and when interacting with their main-chain carbonyl oxygen or nitrogen atom additionally labeled with (O) or (N). Fig. S6. Side chain torsional angles sampled during molecular dynamics simulations. Density plots representing the χ1 and χ2 conformations of W202 (A) and W293 (B). The marginal distributions are obtained using a kernel density estimate. The centroids from a k-means clustering are shown with orange triangles. Fig. S7. Multiple sequence alignment of AdiC from E. coli K12 and the pathogenic E. coli strains O104:H4 and O157:H7, AdiC/CadB homologs (hAdiC/hCadB) from other pathogenic enterobacteria and the amino acid-diamine transporters PotE and CadB from E. coli K12. Amino acid sequence alignment was performed with Clustal Omega ( https://www.ebi.ac.uk/Tools/msa/clustalo/ ). The UniProt ID or NCBI reference sequence codes are as follows: AdiC E. coli K12 (P60061), AdiC E. coli O104:H4 (A0A0E0Y6U0), AdiC E. coli O157:H7 (P60063), PotE E. coli K12 (P0AAF1), CadB E. coli K12 (P0AAE8), hAdiC Salmonella typhi (P60065), hAdiC Shigella flexneri (P60064), hCadB Vibrio cholerae (WP_000097425.1) and hAdiC Yersinia enterocolitica (WP_174848373.1). Positions with a single, fully conserved residue are indicated by (*), conservation between groups of strongly and weakly similar properties are indicated by (:) and (·), respectively. Color-coding of amino acid residues is based on their physicochemical properties, i.e., small and hydrophobic (red), acidic (blue), basic (magenta) and other (green) amino acid residues. The highly conserved gating residues W202 and W293 are highlighted in bold and yellow, and the N- and C-terminal numbers of the corresponding amino acid sequence stretches are indicated. Fig. S8. Cavity at the dimer interface. Two different views into the heart-shaped inter-dimeric cavity are shown, i.e., as viewed from the membrane plane (A) and as viewed from the periplasmic side (B). The top images represent overviews of the overall AdiC structure displayed as transparent surfaces and ribbons. The panels in the middle illustrate a vertical cut through the structure revealing the presence of a buried cavity (highlighted in red). The boxed structural regions are displayed enlarged in the bottom images. In all panels, side chains shaping the cavity are shown as sticks. All structural elements and labels are colored according to the individual monomeric color code, i.e., in blue and yellow. Fig. S9. Water inside the interdimeric cavity. (A) Positive residual Fo-Fc electron density map after the first refinement run. (B) After positioning eight waters (a-c, e-h and j), the second refinement run revealed additional positive residual Fo-Fc electron density. (C) 2Fo-Fc density after the third refinement run with all waters positioned (a-k). (D) Distances between water molecules are shown as black dashed lines and are given in Å. (E) Contour map representing the density probability of the water molecules in the cavity calculated from molecular dynamics simulations. The positions of crystallographic water molecules a-k are indicated with yellow crosses. (F) Corresponding wire-frame rendering of the isosurface contoured at 10% probability. In panels (A-D) and (F), the AdiC structure (transparent ribbons), important amino acid side chains (sticks) and the labels are colored according to the individual monomeric color code, i.e., in blue and yellow. Water molecules are represented as red spheres and are labeled with small case letters. Positive Fo-Fc and 2Fo-Fc electron density maps are represented by meshes, colored in green and blue, and contoured at 3.0 and 1.0 σ, respectively. Fig. S10. Different possibilities of water binding at the AdiC dimer interface cavity, i.e., binding of one (A-D) or two (E-G) water molecules. In all panels, distances are in Å and shown as black dashed lines. The AdiC structure (transparent ribbons), important amino acid side chains (sticks) and the labels are colored according to the individual monomeric color code, i.e., in blue and yellow. Water molecules are represented as red spheres and are labeled with the small case letters a-d. Corresponding frequencies (%) according to molecular dynamics simulations of water configurations are indicated in the lower, left corners. Fig. S11. Size exclusion chromatography (SEC) of AdiC variants. Wild-type AdiC (AdiC-wt), and AdiC mutants Q88E (AdiC-Q88E), Y367F (AdiC-Y367F) and T421V (AdiC-T421V) eluted at similar elution volumes indicating preservation of the dimeric state. SEC analysis was performed as described in Methods for thermostability analysis of AdiC variants. Table S1. Data collection, processing and refinement statistics. Table S2. Selected interactions in the substrate-binding site involving water molecules
- Published
- 2021
- Full Text
- View/download PDF
39. Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization
- Author
-
Friedrich, Nikolas; https://orcid.org/0000-0003-0694-657X, Stiegeler, Emanuel, Glögl, Matthias, Lemmin, Thomas, Hansen, Simon, Kadelka, Claus; https://orcid.org/0000-0002-5712-8529, Wu, Yufan, Ernst, Patrick; https://orcid.org/0000-0001-6037-1856, Maliqi, Liridona, Foulkes, Caio, Morin, Mylène, Eroglu, Mustafa, Liechti, Thomas, Ivan, Branislav, Reinberg, Thomas, Schaefer, Jonas V, Karakus, Umut, Ursprung, Stephan; https://orcid.org/0000-0003-2476-178X, Mann, Axel, Rusert, Peter, Kouyos, Roger D; https://orcid.org/0000-0002-9220-8348, Robinson, John A; https://orcid.org/0000-0001-7857-8556, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Plückthun, Andreas; https://orcid.org/0000-0003-4191-5306, Trkola, Alexandra; https://orcid.org/0000-0003-1013-876X, Friedrich, Nikolas; https://orcid.org/0000-0003-0694-657X, Stiegeler, Emanuel, Glögl, Matthias, Lemmin, Thomas, Hansen, Simon, Kadelka, Claus; https://orcid.org/0000-0002-5712-8529, Wu, Yufan, Ernst, Patrick; https://orcid.org/0000-0001-6037-1856, Maliqi, Liridona, Foulkes, Caio, Morin, Mylène, Eroglu, Mustafa, Liechti, Thomas, Ivan, Branislav, Reinberg, Thomas, Schaefer, Jonas V, Karakus, Umut, Ursprung, Stephan; https://orcid.org/0000-0003-2476-178X, Mann, Axel, Rusert, Peter, Kouyos, Roger D; https://orcid.org/0000-0002-9220-8348, Robinson, John A; https://orcid.org/0000-0001-7857-8556, Günthard, Huldrych F; https://orcid.org/0000-0002-1142-6723, Plückthun, Andreas; https://orcid.org/0000-0003-4191-5306, and Trkola, Alexandra; https://orcid.org/0000-0003-1013-876X
- Abstract
The V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base. Challenging this view, we present V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs) matching the breadth of V3-base bnAbs. While most bnAbs target prefusion Env, V3-crown bnDs bind open Env conformations triggered by CD4 engagement. BnDs achieve breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3. We further show that these V3-crown conformations can, in principle, be attacked by antibodies. Supporting this conclusion, analysis of antibody binding activity in the Swiss 4.5 K HIV-1 cohort (n = 4,281) revealed a co-evolution of V3-crown reactivities and neutralization breadth. Our results indicate a role of V3-crown responses and its conformational preferences in bnAb development to be considered in preventive and therapeutic approaches.
- Published
- 2021
40. In-Depth Analysis of Hyaline Fibromatosis Syndrome Frameshift Mutations at the Same Site Reveal the Necessity of Personalized Therapy
- Author
-
Yan, Shixu E., Lemmin, Thomas, Salvi, Suzanne, Lausch, Ekkehart, Superti-Furga, Andrea, Rokicki, Dariusz, Dal Peraro, Matteo, and van der Goot, Gisou F.
- Published
- 2013
- Full Text
- View/download PDF
41. RosENet: Improving binding affinity prediction by leveraging molecular mechanics energies with a 3D Convolutional Neural Network
- Author
-
Hassan-Harrirou, Hussein, primary, Zhang, Ce, additional, and Lemmin, Thomas, additional
- Published
- 2020
- Full Text
- View/download PDF
42. RosENet: Improving Binding Affinity Prediction by Leveraging Molecular Mechanics Energies with an Ensemble of 3D Convolutional Neural Networks
- Author
-
Hassan-Harrirou, Hussein, primary, Zhang, Ce, additional, and Lemmin, Thomas, additional
- Published
- 2020
- Full Text
- View/download PDF
43. Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein
- Author
-
Lemmin, Thomas, primary, Kalbermatter, David, additional, Harder, Daniel, additional, Plattet, Philippe, additional, and Fotiadis, Dimitrios, additional
- Published
- 2020
- Full Text
- View/download PDF
44. Compressive Sensing Using Iterative Hard Thresholding With Low Precision Data Representation: Theory and Applications
- Author
-
Gurel, Nezihe Merve, primary, Kara, Kaan, additional, Stojanov, Alen, additional, Smith, Tyler, additional, Lemmin, Thomas, additional, Alistarh, Dan, additional, Puschel, Markus, additional, and Zhang, Ce, additional
- Published
- 2020
- Full Text
- View/download PDF
45. MOESM1 of Glycosylator: a Python framework for the rapid modeling of glycans
- Author
-
Lemmin, Thomas and Cinque Soto
- Subjects
carbohydrates (lipids) - Abstract
Additional file 1: Figure S1. Architecture of Glycosylator, a Python framework for the rapid modeling of glycans. Each class is represented by a hexagon. Full circles connecting classes indicate a class that contains an instance of the previous one as an attribute, e.g. instances of Molecule and MoleculeBuilder are attributes of Glycosylator. Several attributes from Glycosylator can be directly shared with Drawer and Sampler (white squares). Glycosylator can parse a PDB file of a glycoprotein and identify all the sequons (orange rhombus). The glycans (blue squares and green circles) will be extracted and saved as Molecule instances. Glycans at each sequon can then be built, modified or identified. Figure S2. Glycosylator Graphical User Interface. a) The main window is used to import a PDB file of a glycoprotein. Glycosylator will produce a symbolic representation (orange dashed line rectangle). A specific sequon can be selected in the right panel (purple dashed line rectangle). The glycan can be modified by clicking on the symbolic representation. b) The user can select a glycan from the common library or a library that they created. The selected glycan is highlighted with a red square. Example S1. Building a glycan. The structure of an N-Acetyl-D-Glucosamine will be imported as a Molecule instance. All missing atoms will be added according to the CHARMM force field. A second N-Acetyl-D-Glucosamine will then be linked through a 1-4 glycosidic bond. Finally, an Alpha-D-added according to the CHARMM force field. A second N-Acetyl-D-Glucosamine will then be linked through a 1-4 glycosidic bond. Finally, an Alpha-D-Mannosewill be built ab initio and saved to a PDB file. Example S2. Importing, identifying and editing of a glycan. The structure of a mannose 9 will be imported as a Molecule instance. A Glycosylator instance will then identify it against a database of known structures. Finally, the Molecule will be trimmed down to a mannose 6.
- Published
- 2019
- Full Text
- View/download PDF
46. Glycosylator: a Python framework for the rapid modeling of glycans
- Author
-
Lemmin, Thomas; https://orcid.org/0000-0001-5705-4964, Soto, Cinque, Lemmin, Thomas; https://orcid.org/0000-0001-5705-4964, and Soto, Cinque
- Abstract
BACKGROUND Carbohydrates are a class of large and diverse biomolecules, ranging from a simple monosaccharide to large multi-branching glycan structures. The covalent linkage of a carbohydrate to the nitrogen atom of an asparagine, a process referred to as N-linked glycosylation, plays an important role in the physiology of many living organisms. Most software for glycan modeling on a personal desktop computer requires knowledge of molecular dynamics to interface with specialized programs such as CHARMM or AMBER. There are a number of popular web-based tools that are available for modeling glycans (e.g., GLYCAM-WEB (http:// https://dev.glycam.org/gp/ ) or Glycosciences.db ( http://www.glycosciences.de/ )). However, these web-based tools are generally limited to a few canonical glycan conformations and do not allow the user to incorporate glycan modeling into their protein structure modeling workflow. RESULTS Here, we present Glycosylator, a Python framework for the identification, modeling and modification of glycans in protein structure that can be used directly in a Python script through its application programming interface (API) or through its graphical user interface (GUI). The GUI provides a straightforward two-dimensional (2D) rendering of a glycoprotein that allows for a quick visual inspection of the glycosylation state of all the sequons on a protein structure. Modeled glycans can be further refined by a genetic algorithm for removing clashes and sampling alternative conformations. Glycosylator can also identify specific three-dimensional (3D) glycans on a protein structure using a library of predefined templates. CONCLUSIONS Glycosylator was used to generate models of glycosylated protein without steric clashes. Since the molecular topology is based on the CHARMM force field, new complex sugar moieties can be generated without modifying the internals of the code. Glycosylator provides more functionality for analyzing and modeling glycans than any other ava
- Published
- 2019
47. Structural heterogeneity and intersubject variability of A beta in familial and sporadic Alzheimer's disease
- Author
-
Condello, Carlo, Lemmin, Thomas, Stöhr, Jan, Nick, Mimi, Wu, Yibing, Maxwell, Alison M., Watts, Joel C., Caro, Christoffer D., Oehler, Abby, Keene, C. Dirk, Bird, Thomas D., van Duinen, Sjoerd G., Lannfelt, Lars, Ingelsson, Martin, Graff, Caroline, Giles, Kurt, DeGrado, William F., Prusiner, Stanley B., Condello, Carlo, Lemmin, Thomas, Stöhr, Jan, Nick, Mimi, Wu, Yibing, Maxwell, Alison M., Watts, Joel C., Caro, Christoffer D., Oehler, Abby, Keene, C. Dirk, Bird, Thomas D., van Duinen, Sjoerd G., Lannfelt, Lars, Ingelsson, Martin, Graff, Caroline, Giles, Kurt, DeGrado, William F., and Prusiner, Stanley B.
- Abstract
Point mutations in the amyloid-beta (A beta) coding region produce a combination of mutant and WT A beta isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant A beta determines WT A beta conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of A beta deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT A beta, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant A beta 40 fibrils into transgenic mice expressing only WT A beta induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant A beta 40 prions induce a conformation of WT A beta similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial A beta prion conformations, which kinetically dominate the spread of prions in the brain.
- Published
- 2018
- Full Text
- View/download PDF
48. Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1
- Author
-
Xu, Kai, primary, Acharya, Priyamvada, additional, Kong, Rui, additional, Cheng, Cheng, additional, Chuang, Gwo-Yu, additional, Liu, Kevin, additional, Louder, Mark K., additional, O’Dell, Sijy, additional, Rawi, Reda, additional, Sastry, Mallika, additional, Shen, Chen-Hsiang, additional, Zhang, Baoshan, additional, Zhou, Tongqing, additional, Asokan, Mangaiarkarasi, additional, Bailer, Robert T., additional, Chambers, Michael, additional, Chen, Xuejun, additional, Choi, Chang W., additional, Dandey, Venkata P., additional, Doria-Rose, Nicole A., additional, Druz, Aliaksandr, additional, Eng, Edward T., additional, Farney, S. Katie, additional, Foulds, Kathryn E., additional, Geng, Hui, additional, Georgiev, Ivelin S., additional, Gorman, Jason, additional, Hill, Kurt R., additional, Jafari, Alexander J., additional, Kwon, Young D., additional, Lai, Yen-Ting, additional, Lemmin, Thomas, additional, McKee, Krisha, additional, Ohr, Tiffany Y., additional, Ou, Li, additional, Peng, Dongjun, additional, Rowshan, Ariana P., additional, Sheng, Zizhang, additional, Todd, John-Paul, additional, Tsybovsky, Yaroslav, additional, Viox, Elise G., additional, Wang, Yiran, additional, Wei, Hui, additional, Yang, Yongping, additional, Zhou, Amy F., additional, Chen, Rui, additional, Yang, Lu, additional, Scorpio, Diana G., additional, McDermott, Adrian B., additional, Shapiro, Lawrence, additional, Carragher, Bridget, additional, Potter, Clinton S., additional, Mascola, John R., additional, and Kwong, Peter D., additional
- Published
- 2018
- Full Text
- View/download PDF
49. Microsecond Dynamics and Network Analysis of the HIV-1 SOSIP Env Trimer Reveal Collective Behavior and Conserved Microdomains of the Glycan Shield
- Author
-
Lemmin, Thomas, primary, Soto, Cinque, additional, Stuckey, Jonathan, additional, and Kwong, Peter D., additional
- Published
- 2017
- Full Text
- View/download PDF
50. Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation
- Author
-
Zhou, Tongqing, primary, Doria-Rose, Nicole A., additional, Cheng, Cheng, additional, Stewart-Jones, Guillaume B.E., additional, Chuang, Gwo-Yu, additional, Chambers, Michael, additional, Druz, Aliaksandr, additional, Geng, Hui, additional, McKee, Krisha, additional, Kwon, Young Do, additional, O’Dell, Sijy, additional, Sastry, Mallika, additional, Schmidt, Stephen D., additional, Xu, Kai, additional, Chen, Lei, additional, Chen, Rita E., additional, Louder, Mark K., additional, Pancera, Marie, additional, Wanninger, Timothy G., additional, Zhang, Baoshan, additional, Zheng, Anqi, additional, Farney, S. Katie, additional, Foulds, Kathryn E., additional, Georgiev, Ivelin S., additional, Joyce, M. Gordon, additional, Lemmin, Thomas, additional, Narpala, Sandeep, additional, Rawi, Reda, additional, Soto, Cinque, additional, Todd, John-Paul, additional, Shen, Chen-Hsiang, additional, Tsybovsky, Yaroslav, additional, Yang, Yongping, additional, Zhao, Peng, additional, Haynes, Barton F., additional, Stamatatos, Leonidas, additional, Tiemeyer, Michael, additional, Wells, Lance, additional, Scorpio, Diana G., additional, Shapiro, Lawrence, additional, McDermott, Adrian B., additional, Mascola, John R., additional, and Kwong, Peter D., additional
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.