Molecular architecture and dynamics of SARS-CoV-2 envelope by integrative modeling

Abstract

Despite tremendous efforts by research community during the COVID-19 pandemic, the exact structure of SARS-CoV-2 and related betacoronaviruses remains elusive. Here, we developed and applied an integrative multi-scale computational approach to model the envelope structure of SARS-CoV-2, focusing on studying the dynamic nature and molecular interactions of its most abundant, but largely understudied, M (membrane) protein. The molecular dynamics simulations allowed us to test the envelop stability under different configurations and revealed that M dimers agglomerated into large, filament-like, macromolecular assemblies with distinct molecular patterns formed by M's transmembrane and intra-virion (endo) domains. These results were in agreement with the experimental data, demonstrating a generic and versatile integrative approach to model the structure of a virus de novo, providing insights into critical roles of structural proteins in the viral assembly and integration, and proposing new targets for the antiviral therapies.

Electrostatic Map of the SARS-CoV-2 Virion Specifies Binding Sites of the Antiviral Cationic Photosensitizer

“…In this study, we used the CG model based on Martini 3 force field of SARS-CoV-2 envelope developed in [28], and kindly provided to us by W. Pezeshkian, D. Korkin and S.-J. Marrink (8 February 2022 version).…”

“…Among the advances in computational virology bringing us closer to creating realistic models of whole virions are: the study of the structural dynamics of viral capsids, by employing a coarse-graining (CG) molecular dynamics method [21]; atomic HIV-1 capsid model [22]; simulation of Herpes simplex virus type 2 B-capsid and chromatin models in GENeralized-Ensemble Simulation System (GENESIS) [23]; a dynamic and integrative computational model of an influenza A virion [24]; computational model of the envelope of the dengue virion [25]; Martini CG models of intact SARS-CoV and SARS-CoV-2 envelopes [26]; and multiscale CG models of the SARS-CoV-2 virion [27,28].…”

“…In this study, we utilized the CG model of SARS-CoV-2 developed in [28], and kindly provided by W. Pezeshkian, D. Korkin and S.J. Marrink, to simulate the interaction of the photosensitizer (PS) octakis(cholinyl)zinc phthalocyanine (ZnPcChol 8+ ) with the surface structures of the whole virion.…”

Correction to “Elucidation of SARS-Cov-2 Budding Mechanisms through Molecular Dynamics Simulations of M and E Protein Complexes”

“…This is consistent with our previous simulation in which the only protein–protein interactions came from a few random contacts between unstructured loops. Since recent studies have suggested that M dimers actually do interact with each other, , we hypothesize that the lack of interactions in our simulation might be due to the simulation’s temperature of 300 K. This temperature is standard for molecular dynamics studies but is lower than human body temperature. Indeed, coarse-grained simulations by Rath et al suggest that lower temperatures might be detrimental to M protein dimer interactions, possibly due to an energy barrier from lipid packing around the dimers .…”

Adsorption of Pulmonary and Exogeneous Surfactants on SARS-CoV-2 Spike Protein

“…4 While viral lysis was observed at high surfactant concentrations that can be cytotoxic, functional inactivation of viral proteins by surfactant adsorption was found at low surfactant concentrations suitable for therapeutic administration. 4 Despite recent great progress in molecular simulations of coronaviruses, including simulations of systems containing several to hundreds of millions of atoms, [14][15][16] no attempts have been made to study the interfacial interactions of SARS-CoV-2 virions with pulmonary and exogenous surfactants that is the focus of this work. Our main goal is to mimic in-silico surfactant adsorption on the S1 domain that is responsible for ACE2 binding.…”