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...

• Autores: Lipskij, Alexander; Arbeitman, Claudia Roxana; Rojas, Pablo; Ojeda-May, Pedro; Garcia, Martin E.
• Año de publicación: 2023
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: SARS-CoV-2; SPIKE PROTEIN; STRUCTURAL STABILITY; MOLECULAR DYNAMICS SIMULATIONS; COVID-19
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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, andGamma 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 10 4 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 conformationdevelops, which exhibits a similar resistance to EF (damage threshold higher than 10 8 V/m) like most globular proteins.
Fil: Lipskij, Alexander. University of Kassel; Alemania
Fil: Arbeitman, Claudia Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Kassel; Alemania. Universidad Tecnologica Nacional. Facultad Regional Buenos Aires. Grupo de Investigacion y Desarrollo En Bioingenieria.; Argentina
Fil: Rojas, Pablo. University of Kassel; Alemania
Fil: Ojeda-May, Pedro. University of Kassel; Alemania
Fil: Garcia, Martin E.. University of Kassel; Alemania