Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 43, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2100943118
Keywords
molecular biophysics; molecular dynamics; virus structure; statistical mechanics; COVID-19
Categories
Funding
- NSF [MCB 2028 443]
- Molecular Science Software Institute seed COVID-19 fellowship - NSF [OAC-1547 580]
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Researchers are focusing on the correlation between the RBD region of the SARS-CoV-2 virus and residues distant from it to understand molecular recognition events and predict key mutations for therapeutics. Their model can identify multiple residues with long-distance coupling with the RBD opening and successfully predict some key mutations.
Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the attachment of the receptor-binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, com-putational and experimental studies that search for therapeu-tics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and preidentifying them can give clues for designing pan-coronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD open-ing. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab initio from our model. Conversely, broad-spectrum therapeutics like drugs and monoclonal antibod-ies can target these key distant-but-conserved regions of the spike protein.
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