Distant residues modulate conformational opening in SARS-CoV-2 spike protein

Area of Science:

• * Virology
• * Structural Biology
• * Computational Biology

Background:

• * Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on spike protein's receptor-binding domain (RBD) binding to host ACE2 receptors.
• * The RBD is a mutation hotspot, leading to drug resistance and challenges in therapeutic development.
• * Current therapeutic strategies primarily focus on the RBD, overlooking potential drug resistance mechanisms.

Purpose of the Study:

• * To investigate long-distance correlations between the RBD and other spike protein residues.
• * To identify key mutations in distant, allosteric sites for therapeutic targeting.
• * To inform the design of pan-coronavirus vaccines against future outbreaks.

Main Methods:

• * Employed time-lagged independent component analysis (tICA).
• * Utilized protein graph connectivity network analysis.
• * Predicted key mutations *ab initio* based on identified long-distance couplings.

Main Results:

• * Identified multiple residues with long-distance coupling to RBD opening.
• * Predicted residues involved in the D614G mutation and the UK variant's A570D mutation.
• * Demonstrated the model's ability to identify functionally significant distant residues.

Conclusions:

• * Targeting conserved, distant allosteric sites on the spike protein offers a promising therapeutic strategy.
• * Understanding these long-distance interactions can guide the development of broad-spectrum antivirals and vaccines.
• * Pre-identifying mutations in conserved regions can anticipate and counter viral evolution.