scholarly journals The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor

2020 ◽  
Author(s):  
Esther S. Brielle ◽  
Dina Schneidman-Duhovny ◽  
Michal Linial
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Cell Receptor ◽  
Host Recognition ◽  
Interface Residue ◽  
Binding Affinities ◽  
Temporal Dimension ◽  
Binding Interface ◽  
Residue Contacts ◽  
Dynamics Simulations

AbstractThe COVID-19 disease has plagued over 110 countries and has resulted in over 4,000 deaths within 10 weeks. We compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue-residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to SARS-CoV. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications on therapeutic strategies.One Sentence SummaryMolecular dynamics simulations reveal a temporal dimension of coronaviruses interactions with the host receptor.

scholarly journals The SARS-CoV-2 Exerts a Distinctive Strategy for Interacting with the ACE2 Human Receptor

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 497 ◽  
Author(s):  
Esther S. Brielle ◽  
Dina Schneidman-Duhovny ◽  
Michal Linial
Keyword(s):  
Cell Receptor ◽  
Host Recognition ◽  
Interface Residue ◽  
Binding Affinities ◽  
Binding Interface ◽  
Residue Contacts ◽  
High Infection ◽  
Dynamics Simulations ◽  
Insight Into ◽  
Human Receptor

The COVID-19 disease has plagued over 200 countries with over three million cases and has resulted in over 200,000 deaths within 3 months. To gain insight into the high infection rate of the SARS-CoV-2 virus, we compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue–residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to the SARS-CoV–ACE2 complex. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications for therapeutic strategies.

scholarly journals Structural variability and concerted motions of the T cell receptor – CD3 complex

2021 ◽  
Author(s):  
Prithvi R. Pandey ◽  
Bartosz Różycki ◽  
Reinhard Lipowsky ◽  
Thomas R. Weikl
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
T Cell Receptor ◽  
Tilt Angle ◽  
Structural Changes ◽  
Cell Receptor ◽  
Transmembrane Helices ◽  
Dynamics Simulations ◽  
Tcr Activation

AbstractWe investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) – CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR – CD3 complex, in particular in the EC interactions of the Cβ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR – CD3 complex revealed in our simulations provide atomistic insights for force-based models of TCR activation, which involve such structural changes in response to tilt-inducing forces on antigen-bound TCRs.

scholarly journals 4094 Structural Determinants of Immunogenicity for Peptide-Based Immunotherapy

2020 ◽  
Vol 4 (s1) ◽  
pp. 16-16
Author(s):  
Jason Devlin ◽  
Jesus Alonso ◽  
Grant Keller ◽  
Sara Bobisse ◽  
Alexandre Harari ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
T Cell Receptor ◽  
Tumor Regression ◽  
Recombinant Expression ◽  
Cell Receptor ◽  
Protein Crystal ◽  
Dynamics Simulations

OBJECTIVES/GOALS: Neoantigen vaccine immunotherapies have shown promise in clinical trials, but identifying which peptides to include in a vaccine remains a challenge. We aim to establish that molecular structural features can help predict which neoantigens to target to achieve tumor regression. METHODS/STUDY POPULATION: Proteins were prepared by recombinant expression in E. coli followed by in vitro refolding. Correctly folded proteins were purified by chromatography. Affinities of protein-protein interactions were measured by surface plasmon resonance (SPR) and thermal stabilities of proteins were determined by differential scanning fluorimetry. All experiments were performed at least in triplicate. Protein crystals were obtained by hanging drop vapor diffusion. The protein crystal structures were solved by molecular replacement and underwent several rounds of automated refinement. Molecular dynamics simulations were performed using the AMBER molecular dynamics package. RESULTS/ANTICIPATED RESULTS: A T cell receptor (TCR) expressed by tumor-infiltrating T cells exhibited a 20-fold stronger binding affinity to the neoantigen peptide compared to the self-peptide. X-ray crystal structures of the peptides with the major histocompatibility complex (MHC) protein demonstrated that a non-mutated residue in the peptide samples different positions with the mutation. The difference in conformations of the non-mutated residue was supported by molecular dynamics simulations. Crystal structures of the TCR engaging both peptide/MHCs suggested that the conformation favored by the mutant peptide was crucial for TCR binding. The TCR bound the neoantigen/MHC with faster binding kinetics. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that the mutation impacts the conformation of another residue in the peptide, and this alteration allows for more favorable T cell receptor binding to the neoantigen. This highlights the potential of non-mutated residues in contributing to neoantigen recognition.

scholarly journals Elucidating the T Cell Receptor Transmembrane Organization via Multi-Scale Molecular Dynamics Simulations

2015 ◽  
Vol 108 (2) ◽  
pp. 558a-559a
Author(s):  
Antreas C. Kalli ◽  
Andre Cohnen ◽  
Oreste Acuto ◽  
Mark S.P. Sansom
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Multi Scale ◽  
Dynamics Simulations

scholarly journals Interrogating RNA-small molecule interactions with structure probing and AI augmented-molecular simulations

2021 ◽  
Author(s):  
Yihang Wang ◽  
Shaifaly Parmar ◽  
John S. Schneekloth ◽  
Pratyush Tiwary
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Ligand Recognition ◽  
Binding Affinities ◽  
Structure Probing ◽  
Mutational Profiling ◽  
In Vitro Measurements ◽  
Molecule Interactions ◽  
Dynamics Simulations

While there is increasing interest in the study of RNA as a therapeutic target, efforts to understand RNA-ligand recognition at the molecular level lag far behind our understanding of protein-ligand recognition. This problem is complicated due to the more than ten orders of magnitude in timescales involved in RNA dynamics and ligand binding events, making it not straightforward to design experiments or simulations. Here we make use of artificial intelligence (AI)-augmented molecular dynamics simulations to directly observe ligand dissociation for cognate and synthetic ligands from a riboswitch system. The site-specific flexibility profiles from our simulations are in excellent agreement with in vitro measurements of flexibility using Selective 2' Hydroxyl Acylation analyzed by Primer Extension and Mutational Profiling (SHAPE-MaP). Our simulations reproduce known binding affinity profiles for the cognate and synthetic ligands, and pinpoint how both ligands make use of different aspects of riboswitch flexibility. On the basis of our dissociation trajectories, we also make and validate predictions of pairs of mutations for both the ligand systems that would show differing binding affinities. These mutations are distal to the binding site and could not have been predicted solely on the basis of structure. The methodology demonstrated here shows how molecular dynamics simulations with all-atom force-fields have now come of age in making predictions that complement existing experimental techniques and illuminate aspects of systems otherwise not trivial to understand.

scholarly journals Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

2021 ◽  
Vol 8 ◽  
Author(s):  
Sugunadevi Sakkiah ◽  
Wenjing Guo ◽  
Bohu Pan ◽  
Zuowei Ji ◽  
Gokhan Yavas ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Homology Modeling ◽  
Molecular Dynamics Simulations ◽  
Host Cell ◽  
Tertiary Structure ◽  
Cell Receptor ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Protein ◽  
Dynamics Simulations

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). As of October 21, 2020, more than 41.4 million confirmed cases and 1.1 million deaths have been reported. Thus, it is immensely important to develop drugs and vaccines to combat COVID-19. The spike protein present on the outer surface of the virion plays a major role in viral infection by binding to receptor proteins present on the outer membrane of host cells, triggering membrane fusion and internalization, which enables release of viral ssRNA into the host cell. Understanding the interactions between the SARS-CoV-2 trimeric spike protein and its host cell receptor protein, angiotensin converting enzyme 2 (ACE2), is important for developing drugs and vaccines to prevent and treat COVID-19. Several crystal structures of partial and mutant SARS-CoV-2 spike proteins have been reported; however, an atomistic structure of the wild-type SARS-CoV-2 trimeric spike protein complexed with ACE2 is not yet available. Therefore, in our study, homology modeling was used to build the trimeric form of the spike protein complexed with human ACE2, followed by all-atom molecular dynamics simulations to elucidate interactions at the interface between the spike protein and ACE2. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and in silico alanine scanning were employed to characterize the interacting residues at the interface. Twenty interacting residues in the spike protein were identified that are likely to be responsible for tightly binding to ACE2, of which five residues (Val445, Thr478, Gly485, Phe490, and Ser494) were not reported in the crystal structure of the truncated spike protein receptor binding domain (RBD) complexed with ACE2. These data indicate that the interactions between ACE2 and the tertiary structure of the full-length spike protein trimer are different from those between ACE2 and the truncated monomer of the spike protein RBD. These findings could facilitate the development of drugs and vaccines to prevent SARS-CoV-2 infection and combat COVID-19.

Molecular Simulations to Rationalize Humanized Ab2/3H6 Activity

2011 ◽  
Vol 64 (7) ◽  
pp. 900 ◽  
Author(s):  
Anita de Ruiter ◽  
Alexander Mader ◽  
Renate Kunert ◽  
Chris Oostenbrink
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Heavy Chain ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Dynamics Simulations ◽  
Idiotypic Antibody ◽  
Mouse Antibody ◽  
Hiv 1

The murine anti-idiotypic antibody 3H6 (Ab2/3H6) is directed against the human 2F5 antibody, which is capable of neutralizing HIV-1. Recently, four humanized Ab2/3H6 models have been developed in order to reduce the risk of human anti-mouse antibody (HAMA) responses in case of administration to humans. In this study, molecular dynamics simulations were performed on these models as well as on the murine Ab2/3H6 in solution and bound to 2F5, in order to rationalize the differences in binding affinities of the models towards 2F5. Analysis of these simulations suggested that the orientation and dynamics of the residues TYR54 and TYR103 of the heavy chain of Ab2/3H6 play an important role in these differences. Subsequently, the contribution of these residues to the binding affinity was quantified by applying free energy calculations.

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