Dramatic Differences between the Structural Susceptibility of the S1 Pre- and S2 Postfusion States of the SARS-CoV-2 Spike Protein to External Electric Fields Revealed by Molecular Dynamics Simulations
Author:
Lipskij Alexander1, Arbeitman Claudia123, Rojas Pablo1ORCID, Ojeda-May Pedro4ORCID, Garcia Martin E.1ORCID
Affiliation:
1. Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, FB10, Universität Kassel, Heinrich-Plett-Str. 40, 34132 Kassel, Germany 2. CONICET Consejo Nacional de Investigaciones Científicas y Técnicas, Godoy Cruz 2290, Buenos Aires C1425FQB, Argentina 3. GIBIO-Universidad Tecnológica Nacional-Facultad Regional Buenos Aires, Medrano 951, Buenos Aires C1179AAQ, Argentina 4. High Performance Computing Center North (HPC2N), Umeå University, S-90187 Umeå, Sweden
Abstract
In its prefusion state, the SARS-CoV-2 spike protein (similarly to other class I viral fusion proteins) is metastable, which is considered to be an important feature for optimizing or regulating its functions. After the binding process of its S1 subunit (S1) with ACE2, the spike protein (S) undergoes a dramatic conformational change where S1 splits from the S2 subunit, which then penetrates the membrane of the host cell, promoting the fusion of the viral and cell membranes. This results in the infection of the host cell. In a previous work, we showed—using large-scale molecular dynamics simulations—that the application of external electric fields (EFs) induces drastic changes and damage in the receptor-binding domain (RBD) of the wild-type spike protein, as well of the Alpha, Beta, and Gamma variants, leaving a structure which cannot be recognized anymore by ACE2. In this work, we first extend the study to the Delta and Omicron variants and confirm the high sensitivity and extreme vulnerability of the RBD of the prefusion state of S to moderate EF (as weak as 104 V/m), but, more importantly, we also show that, in contrast, the S2 subunit of the postfusion state of the spike protein does not suffer structural damage even if electric field intensities four orders of magnitude higher are applied. These results provide a solid scientific basis to confirm the connection between the prefusion-state metastability of the SARS-CoV-2 spike protein and its susceptibility to be damaged by EF. After the virus docks to the ACE2 receptor, the stable and robust postfusion conformation develops, which exhibits a similar resistance to EF (damage threshold higher than 108 V/m) like most globular proteins.
Subject
Virology,Infectious Diseases
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