Ionization of D571 Is Coupled with SARS-CoV-2 Spike Up/Down Equilibrium Revealing the pH-Dependent Allosteric Mechanism of Receptor-Binding Domains.
J Phys Chem B
; 126(26): 4828-4839, 2022 07 07.
Article
in English
| MEDLINE | ID: covidwho-1900410
ABSTRACT
As a type I viral fusion protein, SARS-CoV-2 spike undergoes a pH-dependent switch to mediate the endosomal positioning of the receptor-binding domain to facilitate viral entry into cells and immune evasion. Gaps in our knowledge concerning the conformational transitions and key intramolecular motivations have hampered the development of effective therapeutics against the virus. To clarify the pH-sensitive elements on spike-gating the receptor-binding domain (RBD) opening and understand the details of the RBD opening transition, we performed microsecond-time scale constant pH molecular dynamics simulations in this study. We identified the deeply buried D571 with a clear pKa shift, suggesting a potential pH sensor, and showed the coupling of ionization of D571 with spike RBD-up/down equilibrium. We also computed the free-energy landscape for RBD opening and identified the crucial interactions that influence RBD dynamics. The atomic-level characterization of the pH-dependent spike activation mechanism provided herein offers new insights for a better understanding of the fundamental mechanisms of SARS-CoV-2 viral entry and infection and hence supports the discovery of novel therapeutics for COVID-19.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
SARS-CoV-2
/
COVID-19
Limits:
Humans
Language:
English
Journal:
J Phys Chem B
Journal subject:
Chemistry
Year:
2022
Document Type:
Article
Affiliation country:
Acs.jpcb.2c02365
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