76 results on '"Lemmin, Thomas"'
Search Results
52. Insights into the Dynamics of the HIV-1 Env Glycan Shield
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Lemmin, Thomas, primary, Soto, Cinque, additional, and Kwong, Peter D., additional
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- 2017
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53. Effect of the Synaptic Plasma Membrane on the Stability of the Amyloid Precursor Protein Homodimer
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Audagnotto, Martina, primary, Lemmin, Thomas, additional, Barducci, Alessandro, additional, and Dal Peraro, Matteo, additional
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- 2016
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54. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G
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Stewart-Jones, Guillaume B.E., primary, Soto, Cinque, additional, Lemmin, Thomas, additional, Chuang, Gwo-Yu, additional, Druz, Aliaksandr, additional, Kong, Rui, additional, Thomas, Paul V., additional, Wagh, Kshitij, additional, Zhou, Tongqing, additional, Behrens, Anna-Janina, additional, Bylund, Tatsiana, additional, Choi, Chang W., additional, Davison, Jack R., additional, Georgiev, Ivelin S., additional, Joyce, M. Gordon, additional, Kwon, Young Do, additional, Pancera, Marie, additional, Taft, Justin, additional, Yang, Yongping, additional, Zhang, Baoshan, additional, Shivatare, Sachin S., additional, Shivatare, Vidya S., additional, Lee, Chang-Chun D., additional, Wu, Chung-Yi, additional, Bewley, Carole A., additional, Burton, Dennis R., additional, Koff, Wayne C., additional, Connors, Mark, additional, Crispin, Max, additional, Baxa, Ulrich, additional, Korber, Bette T., additional, Wong, Chi-Huey, additional, Mascola, John R., additional, and Kwong, Peter D., additional
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- 2016
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55. Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design
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Gorman, Jason, primary, Soto, Cinque, additional, Yang, Max M, additional, Davenport, Thaddeus M, additional, Guttman, Miklos, additional, Bailer, Robert T, additional, Chambers, Michael, additional, Chuang, Gwo-Yu, additional, DeKosky, Brandon J, additional, Doria-Rose, Nicole A, additional, Druz, Aliaksandr, additional, Ernandes, Michael J, additional, Georgiev, Ivelin S, additional, Jarosinski, Marissa C, additional, Joyce, M Gordon, additional, Lemmin, Thomas M, additional, Leung, Sherman, additional, Louder, Mark K, additional, McDaniel, Jonathan R, additional, Narpala, Sandeep, additional, Pancera, Marie, additional, Stuckey, Jonathan, additional, Wu, Xueling, additional, Yang, Yongping, additional, Zhang, Baoshan, additional, Zhou, Tongqing, additional, Program, NISC Comparative Sequencing, additional, Mullikin, James C, additional, Baxa, Ulrich, additional, Georgiou, George, additional, McDermott, Adrian B, additional, Bonsignori, Mattia, additional, Haynes, Barton F, additional, Moore, Penny L, additional, Morris, Lynn, additional, Lee, Kelly K, additional, Shapiro, Lawrence, additional, Mascola, John R, additional, and Kwong, Peter D, additional
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- 2015
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56. LipidBuilder: A Framework To Build Realistic Models for Biological Membranes
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Bovigny, Christophe, primary, Tamò, Giorgio, additional, Lemmin, Thomas, additional, Maïno, Nicolas, additional, and Dal Peraro, Matteo, additional
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- 2015
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57. Palmitoylated calnexin is a key component of the ribosome-translocon complex
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Lakkaraju, Asvin K K, Abrami, Laurence, Lemmin, Thomas, Blaskovic, Sanja, Kunz, Béatrice, Kihara, Akio, Dal Peraro, Matteo, van der Goot, Françoise Gisou, University of Zurich, and van der Goot, Françoise Gisou
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Protein Folding ,Receptors, Peptide ,Lipoylation ,Receptors, Cytoplasmic and Nuclear ,Genetics and Molecular Biology ,macromolecular substances ,calnexin ,Endoplasmic Reticulum ,environment and public health ,Article ,endoplasmic reticulum folding ,SX08 LipidX ,Dhhc6 ,Er ,SX00 SystemsX.ch ,1300 General Biochemistry, Genetics and Molecular Biology ,2400 General Immunology and Microbiology ,1312 Molecular Biology ,Humans ,palmitoylation ,Gene Silencing ,Endoplasmic-Reticulum ,Molecular Biology ,Cytoskeleton ,Glycoproteins ,Molecular-Dynamics ,Membrane Glycoproteins ,General Immunology and Microbiology ,Protein Stability ,Protein ,General Neuroscience ,Calcium-Binding Proteins ,Membrane ,2800 General Neuroscience ,Endocytosis ,Mammalian-Cells ,Localization ,General Biochemistry ,570 Life sciences ,biology ,lipids (amino acids, peptides, and proteins) ,Protein Processing, Post-Translational ,Ribosomes ,Acyltransferases ,HeLa Cells ,Receptor - Abstract
A third of the human genome encodes N-glycosylated proteins. These are co-translationally translocated into the lumen/membrane of the endoplasmic reticulum (ER) where they fold and assemble before they are transported to their final destination. Here, we show that calnexin, a major ER chaperone involved in glycoprotein folding is palmitoylated and that this modification is mediated by the ER palmitoyltransferase DHHC6. This modification leads to the preferential localization of calnexin to the perinuclear rough ER, at the expense of ER tubules. Moreover, palmitoylation mediates the association of calnexin with the ribosome-translocon complex (RTC) leading to the formation of a supercomplex that recruits the actin cytoskeleton, leading to further stabilization of the assembly. When formation of the calnexin-RTC supercomplex was affected by DHHC6 silencing, mutation of calnexin palmitoylation sites or actin depolymerization, folding of glycoproteins was impaired. Our findings thus show that calnexin is a stable component of the RTC in a manner that is exquisitely dependent on its palmitoylation status. This association is essential for the chaperone to capture its client proteins as they emerge from the translocon, acquire their N-linked glycans and initiate folding. The EMBO Journal (2012) 31, 1823-1835. doi: 10.1038/emboj.2012.15; Published online 7 February 2012
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- 2012
58. De novo design of covalently constrained mesosize protein scaffolds with unique tertiary structures.
- Author
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Bobo Dang, Haifan Wu, Mulligan, Vikram Khipple, Mravic, Marco, Yibing Wu, Lemmin, Thomas, Ford, Alexander, Silva, Daniel-Adriano, Baker, David, and DeGrado, William F.
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COVALENT bonds ,PROTEIN engineering ,PROTEIN synthesis ,PROTEIN-protein interactions ,CROSSLINKING site (Polymers) - 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. [ABSTRACT FROM AUTHOR]
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- 2017
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59. Reaction Mechanism and Catalytic Fingerprint of Allantoin Racemase
- Author
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Bovigny, Christophe, primary, Degiacomi, Matteo Thomas, additional, Lemmin, Thomas, additional, Dal Peraro, Matteo, additional, and Stenta, Marco, additional
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- 2014
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60. Perturbations of the Straight Transmembrane α-Helical Structure of the Amyloid Precursor Protein Affect Its Processing by γ-Secretase
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Lemmin, Thomas, primary, Dimitrov, Mitko, additional, Fraering, Patrick C., additional, and Dal Peraro, Matteo, additional
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- 2014
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61. The Amyloid Precursor Protein Maintains an Ideal&Alpha-Helical Conformation in the Lipid Bilayer
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Lemmin, Thomas, primary, Dimitrov, Mitko, additional, Fraering, Patrick, additional, and Dal Peraro, Matteo, additional
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- 2014
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62. Palmitoylated calnexin is a key component of the ribosome-translocon complex.
- Author
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Lakkaraju, Asvin K K; https://orcid.org/0000-0001-8752-148X, Abrami, Laurence, Lemmin, Thomas, Blaskovic, Sanja, Kunz, Béatrice, Kihara, Akio, Dal Peraro, Matteo, van der Goot, Françoise Gisou, Lakkaraju, Asvin K K; https://orcid.org/0000-0001-8752-148X, Abrami, Laurence, Lemmin, Thomas, Blaskovic, Sanja, Kunz, Béatrice, Kihara, Akio, Dal Peraro, Matteo, and van der Goot, Françoise Gisou
- Abstract
A third of the human genome encodes N-glycosylated proteins. These are co-translationally translocated into the lumen/membrane of the endoplasmic reticulum (ER) where they fold and assemble before they are transported to their final destination. Here, we show that calnexin, a major ER chaperone involved in glycoprotein folding is palmitoylated and that this modification is mediated by the ER palmitoyltransferase DHHC6. This modification leads to the preferential localization of calnexin to the perinuclear rough ER, at the expense of ER tubules. Moreover, palmitoylation mediates the association of calnexin with the ribosome-translocon complex (RTC) leading to the formation of a supercomplex that recruits the actin cytoskeleton, leading to further stabilization of the assembly. When formation of the calnexin-RTC supercomplex was affected by DHHC6 silencing, mutation of calnexin palmitoylation sites or actin depolymerization, folding of glycoproteins was impaired. Our findings thus show that calnexin is a stable component of the RTC in a manner that is exquisitely dependent on its palmitoylation status. This association is essential for the chaperone to capture its client proteins as they emerge from the translocon, acquire their N-linked glycans and initiate folding.
- Published
- 2012
63. Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
- Author
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Dimitrov, Mitko, primary, Alattia, Jean-René, additional, Lemmin, Thomas, additional, Lehal, Rajwinder, additional, Fligier, Andrzej, additional, Houacine, Jemila, additional, Hussain, Ishrut, additional, Radtke, Freddy, additional, Dal Peraro, Matteo, additional, Beher, Dirk, additional, and Fraering, Patrick C., additional
- Published
- 2013
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64. Intrinsic Transmembrane Flexibility of the Amyloid Precursor Protein Explored by Molecular Simulations
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Lemmin, Thomas, primary, Dimitrov, Mitko, additional, Fraering, Patrick, additional, and Dal Peraro, Matteo, additional
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- 2013
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65. Cardiolipin Models for Molecular Simulations of Bacterial and Mitochondrial Membranes
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Lemmin, Thomas, primary, Bovigny, Christophe, additional, Lançon, Diane, additional, and Dal Peraro, Matteo, additional
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- 2012
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66. Palmitoylated calnexin is a key component of the ribosome-translocon complex
- Author
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Lakkaraju, Asvin KK, primary, Abrami, Laurence, additional, Lemmin, Thomas, additional, Blaskovic, Sanja, additional, Kunz, Béatrice, additional, Kihara, Akio, additional, Dal Peraro, Matteo, additional, and van der Goot, Françoise Gisou, additional
- Published
- 2012
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67. Assembly and Function of the Transmembrane Domain of the Two-Component System PhoQ from E.coli
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Dal Peraro, Matteo, primary and Lemmin, Thomas, additional
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- 2011
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68. Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design
- Author
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Gorman, Jason, Soto, Cinque, Yang, Max M, Davenport, Thaddeus M, Guttman, Miklos, Bailer, Robert T, Chambers, Michael, Chuang, Gwo-Yu, DeKosky, Brandon J, Doria-Rose, Nicole A, Druz, Aliaksandr, Ernandes, Michael J, Georgiev, Ivelin S, Jarosinski, Marissa C, Joyce, M Gordon, Lemmin, Thomas M, Leung, Sherman, Louder, Mark K, McDaniel, Jonathan R, Narpala, Sandeep, Pancera, Marie, Stuckey, Jonathan, Wu, Xueling, Yang, Yongping, Zhang, Baoshan, Zhou, Tongqing, Program, NISC Comparative Sequencing, Mullikin, James C, Baxa, Ulrich, Georgiou, George, McDermott, Adrian B, Bonsignori, Mattia, Haynes, Barton F, Moore, Penny L, Morris, Lynn, Lee, Kelly K, Shapiro, Lawrence, Mascola, John R, and Kwong, Peter D
- Abstract
Broadly neutralizing antibodies (bNAbs) against HIV-1 Env V1V2 arise in multiple donors. However, atomic-level interactions had previously been determined only with antibodies from a single donor, thus making commonalities in recognition uncertain. Here we report the cocrystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third donor. These V1V2-directed bNAbs used strand-strand interactions between a protruding antibody loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Altogether, the multidonor information suggested that V1V2-directed bNAbs form an 'extended class', for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class.
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- 2016
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69. ReactionMechanism and Catalytic Fingerprint of AllantoinRacemase.
- Author
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Bovigny, Christophe, Degiacomi, Matteo Thomas, Lemmin, Thomas, Dal Peraro, Matteo, and Stenta, Marco
- Published
- 2014
- Full Text
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70. Cardiolipin Models for Molecular Simulations of Bacterial and Mitochondrial Membranes
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Lemmin, Thomas, Bovigny, Christophe, Lançon, Diane, and Dal Peraro, Matteo
- Abstract
Present in bacterial and mitochondrial membranes, cardiolipins have a unique dimeric structure, which carries up to two charges (i.e., one per phosphate group) and, under physiological conditions, can be unprotonated or singly protonated. Exhaustive models and characterization of cardiolipins are to date scarce; therefore we propose an ab initioparametrization of cardiolipin species for molecular simulation consistent with commonly used force fields. Molecular dynamics simulations using these models indicate a protonation dependent lipid packing. A peculiar interaction with solvating mono- and divalent cations is also observed. The proposed models will contribute to the study of the assembly of more realistic bacterial and mitochondrial membranes and the investigation of the role of cardiolipins for the biophysical and biochemical properties of membranes and membrane-embedded proteins.
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- 2013
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71. Molecular Modeling of Membrane Embedded Proteins
- Author
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Lemmin, Thomas and Dal Peraro, Matteo
- Subjects
antimicrobial peptides ,molecular modeling ,two-component system ,PhoQ ,Amyloid Precursor Protein ,integrative modeling ,membrane-protein ,cardiolipin ,Alzheimer's ,membrane ,molecular dynamics - Abstract
Over the past years, molecular modeling and simulation techniques have had a major impact on experimental life sciences. They are capable of providing accurate insight into microscopic mechanisms, which are usually difficult to investigate experimentally. Moreover, the integration of experimental data with molecular modeling appears to be a promising strategy to better understand complex biological processes. In this thesis, molecular dynamics simulation has been used in combination with experimental data to investigate two transmembrane proteins: (i) the bacterial chemoreceptor PhoQ and (ii) the Amyloid Precursor Protein (APP). (i) Bacterial two-component system PhoQ and bacterial membranes. Two-component systems (TCSs) are signaling complexes essential for bacterial survival and virulence. PhoQ is the histidine kinase chemoreceptor of the PhoQ-PhoP tandem machine that detects the concentration of cationic species at the inner membrane of Gram-negative bacteria. A full understanding of the PhoQ signal transduction mechanism is currently hindered by the lack of a complete atomistic structure. In this thesis project, the first structural model of the transmembrane (TM) portion of PhoQ from Escherichia coli was assembled, by using molecular simulations integrated with cross-linking disulfide scanning data. Its structural and dynamic features induce a concerted displacement of the TM helices at the periplasmic side, which modulates a rotation at the cytoplasmic end. This supports the idea that signal transduction is promoted through a combination of scissoring and rotational movements of the TM helices. Knowledge of this complex mechanism is essential in order to understand how the chemical stimuli sensed by the periplasmic sensor domain trigger, via the relay of the HAMP domain, the histidine auto-phosphorylation and kinase/phosphatase activity at the cytoplasmic end. The PhoQ sensor domain lies in close proximity to the membrane. Interaction with anionic lipids, such as phosphophatidylglycerols (PG) and cardiolipins (CL), are thought to play a key role in PhoQ activity. Present in bacterial and mitochondrial membranes, cardiolipins have a unique dimeric structure, which carries up to two charges, i.e. one per phosphate group, and under physiological conditions, can be unprotonated or singly protonated. Exhaustive models and characterization of cardiolipins are to-date scarce; therefore an ab initio parameterization of cardiolipin species for molecular simulation consistent with commonly used force fields is proposed here. Molecular dynamics (MD) simulations based on these models indicate a protonation-dependent lipid packing. A noteworthy interaction with solvating mono- and divalent cations is also observed. The proposed models will contribute to the biophysical and biochemical characterizations of bacterial and mitochondrial membranes and membrane-embedded proteins. (ii) Structural and dynamic properties of the Amyloid Precursor Protein. The Amyloid Precursor Protein (APP) is a type I membrane glycoprotein present at the neuronal synapsis. The proteolytic cleavage of its C-terminal segment produces amyloid-β (Aβ) peptides of different lengths, the deposition of which is an early indicator of Alzheimer"s disease (AD). Recently, the backbone structure of the APP transmembrane (TM) domain in detergent micelles was determined by nuclear magnetic resonance (NMR, independently by two different experimental groups). The TM conformations of these two structures are however markedly different. One is characterized by a highly kinked α-helix, whereas the other is mainly straight. Molecular dynamics simulations showed that the APP TM region is highly flexible and its secondary structure is influenced by the surrounding lipid environment. The size of the embedding detergent micelles strongly affects the conformation of the APP α-helix, with solvation being the main driving force for the development of a helical curvature. Once embedded in a membrane bilayer, APP systematically prefers a straight helical conformation. This is also confirmed when analyzing in silico the atomistic APP population observed in double electron-electron resonance (DEER) spectroscopy. In summary, the APP transmembrane domain is highly flexible due to the presence of glycine residues and can readily respond to the lipid environment, a property that might be critical for proteolytic processing by γ-secretase enzymes. The presented thesis work clearly shows how molecular simulations and their interplay with available experimental input can help advance the understanding of the mechanism of complex biological systems and processes on a molecular scale. These results, in particular, go well beyond the current understanding of the functioning of two transmembrane proteins relevant for human health. Furthermore, the computational approaches and procedures developed in these projects will hopefully promote novel integrated strategies for investigating biological systems.
72. Perturbations of the Straight Transmembrane alpha-Helical Structure of the Amyloid Precursor Protein Affect Its Processing by gamma-Secretase
- Author
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Lemmin, Thomas, Dimitrov, Mitko, Fraering, Patrick C., and Dal Peraro, Matteo
- Subjects
Amyloid ,electron paramagnetic resonance (EPR) spectroscopy ,Mass Spectrometry (MS) ,double electron-electron resonance (DEER) ,mental disorders ,Amyloid Precursor Protein ,Secretases ,Molecular Dynamics ,metadynamics - Abstract
Background: Amyloid- neurotoxicity depends on the specificity of the proteolytic cleavage of the amyloid precursor protein (APP) transmembrane domain. Results: The APP transmembrane -helix is straight in a biological membrane bilayer. Conclusion: The flexibility of APP is key for adapting to the lipid environment and modulating proteolytic processing by -secretase. Significance: The dynamic characterization of APP is expected to rationalize the design of -secretase modulators. The amyloid precursor protein (APP) is a widely expressed type I transmembrane (TM) glycoprotein present at the neuronal synapse. The proteolytic cleavage by -secretase of its C-terminal fragment produces amyloid- (A) peptides of different lengths, the deposition of which is an early indicator of Alzheimer disease. At present, there is no consensus on the conformation of the APP-TM domain at the biological membrane. Although structures have been determined by NMR in detergent micelles, their conformation is markedly different. Here we show by using molecular simulations that the APP-TM region systematically prefers a straight -helical conformation once embedded in a membrane bilayer. However, APP-TM is highly flexible, and its secondary structure is strongly influenced by the surrounding lipid environment, as when enclosed in detergent micelles. This behavior is confirmed when analyzing in silico the atomistic APP-TM population observed by residual dipolar couplings and double electron-electron resonance spectroscopy. These structural and dynamic features are critical in the proteolytic processing of APP by the -secretase enzyme, as suggested by a series of Gly(700) mutants. Affecting the hydration and flexibility of APP-TM, these mutants invariantly show an increase in the production of A38 compared with A40 peptides, which is reminiscent of the effect of -secretase modulators inhibitors.
73. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody.
- Author
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Rui Kong, Kai Xu, Tongqing Zhou, Acharya, Priyamvada, Lemmin, Thomas, Kevin Liu, Ozorowski, Gabriel, Soto, Cinque, Taft, Justin D., Bailer, Robert T., Cale, Evan M., Lei Chen, Choi, Chang W., Gwo-Yu Chuang, Doria-Rose, Nicole A., Druz, Aliaksandr, Georgiev, Ivelin S., Gorman, Jason, Jinghe Huang, and Gordon Joyce, M.
- Subjects
- *
HIV antibodies , *PEPTIDES , *GLYCANS , *HIV , *VIRAL antibodies - Abstract
The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed.These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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74. RosENet: Improving binding affinity prediction by leveraging molecular mechanics energies with an ensemble of 3D convolutional neural networks
- Author
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Ce Zhang, Hussein Hassan-Harrirou, Thomas Lemmin, University of Zurich, and Lemmin, Thomas
- Subjects
10028 Institute of Medical Virology ,Computer science ,General Chemical Engineering ,610 Medicine & health ,1600 General Chemistry ,Molecular Dynamics Simulation ,Library and Information Sciences ,Ligands ,01 natural sciences ,Convolutional neural network ,Force field (chemistry) ,Molecular dynamics ,Robustness (computer science) ,Molecular descriptor ,0103 physical sciences ,1706 Computer Science Applications ,Humans ,1500 General Chemical Engineering ,Databases, Protein ,Virtual screening ,010304 chemical physics ,Ensemble forecasting ,Artificial neural network ,Proteins ,General Chemistry ,0104 chemical sciences ,Computer Science Applications ,010404 medicinal & biomolecular chemistry ,570 Life sciences ,biology ,Neural Networks, Computer ,3309 Library and Information Sciences ,Biological system - Abstract
The worldwide increase and proliferation of drug resistant microbes, coupled with the lag in new drug development, represents a major threat to human health. In order to reduce the time and cost for exploring the chemical search space, drug discovery increasingly relies on computational biology approaches. One key step in these approaches is the need for the rapid and accurate prediction of the binding affinity for potential leads. Here, we present RosENet (Rosetta Energy Neural Networks), an ensemble of three-dimensional (3D) Convolutional Neural Networks (CNNs), which combines voxelized molecular mechanics energies and molecular descriptors for predicting the absolute binding affinity of protein–ligand complexes. By leveraging the physicochemical properties captured by the molecular force field, our ensemble model achieved a Root Mean Square Error (RMSE) of 1.24 on the PDBBind v2016 core set. We also explored some limitations and the robustness of the PDBBind data set and our approach on nearly 500 structures, including structures determined by Nuclear Magnetic Resonance and virtual screening experiments. Our study demonstrated that molecular mechanics energies can be voxelized and used to help improve the predictive power of the CNNs. In the future, our framework can be extended to features extracted from other biophysical and biochemical models, such as molecular dynamics simulations., Journal of Chemical Information and Modeling, 60 (6), ISSN:1549-9596, ISSN:0095-2338, ISSN:1520-5142
- Published
- 2020
75. Glycosylator: a Python framework for the rapid modeling of glycans
- Author
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Cinque Soto, Thomas Lemmin, University of Zurich, and Lemmin, Thomas
- Subjects
10028 Institute of Medical Virology ,Glycosylation ,1303 Biochemistry ,computer.software_genre ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,1315 Structural Biology ,Protein structure ,2604 Applied Mathematics ,N-linked glycosylation ,Structural Biology ,Biomolecular modeling ,lcsh:QH301-705.5 ,Graphical user interface ,0303 health sciences ,010304 chemical physics ,biology ,Application programming interface ,Applied Mathematics ,Glycan modeling ,Glycoprotein ,Computer Science Applications ,lcsh:R858-859.7 ,Glycoinformatics ,Web server ,Glycan ,610 Medicine & health ,Computational biology ,Molecular Dynamics Simulation ,lcsh:Computer applications to medicine. Medical informatics ,03 medical and health sciences ,Polysaccharides ,0103 physical sciences ,1312 Molecular Biology ,1706 Computer Science Applications ,Molecular Biology ,Glycoproteins ,030304 developmental biology ,business.industry ,carbohydrates (lipids) ,lcsh:Biology (General) ,chemistry ,biology.protein ,570 Life sciences ,business ,computer ,Software - 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 available software or webserver at present. Glycosylator will be a valuable tool for the glycoinformatics and biomolecular modeling communities., BMC Bioinformatics, 20 (1), ISSN:1471-2105
- Published
- 2019
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76. TemBERTure: advancing protein thermostability prediction with deep learning and attention mechanisms.
- Author
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Rodella C, Lazaridi S, and Lemmin T
- Abstract
Motivation: Understanding protein thermostability is essential for numerous biotechnological applications, but traditional experimental methods are time-consuming, expensive, and error-prone. Recently, deep learning (DL) techniques from natural language processing (NLP) was extended to the field of biology, since the primary sequence of proteins can be viewed as a string of amino acids that follow a physicochemical grammar., Results: In this study, we developed TemBERTure, a DL framework that predicts thermostability class and melting temperature from protein sequences. Our findings emphasize the importance of data diversity for training robust models, especially by including sequences from a wider range of organisms. Additionally, we suggest using attention scores from Deep Learning models to gain deeper insights into protein thermostability. Analyzing these scores in conjunction with the 3D protein structure can enhance understanding of the complex interactions among amino acid properties, their positioning, and the surrounding microenvironment. By addressing the limitations of current prediction methods and introducing new exploration avenues, this research paves the way for more accurate and informative protein thermostability predictions, ultimately accelerating advancements in protein engineering., Availability and Implementation: TemBERTure model and the data are available at: https://github.com/ibmm-unibe-ch/TemBERTure., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)
- Published
- 2024
- Full Text
- View/download PDF
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