Spike Protein Mutation-Induced Changes in the Kinetic and Thermodynamic Behavior of Its Receptor Binding Domains Explain Their Higher Propensity to Attain Open States in SARS-CoV-2 Variants of Concern.
ACS Cent Sci
; 9(10): 1894-1904, 2023 Oct 25.
Article
in En
| MEDLINE
| ID: mdl-37901170
ABSTRACT
Spike (S) protein opening in SARS-CoV-2 controls the accessibility of its receptor binding domains (RBDs) to host receptors and immune recognition. Along the evolution of SARS-CoV-2 to its variants of concern (VOC)-alpha, beta, gamma, delta, and omicron-their S proteins showed a higher propensity to attain open states. Deciphering how mutations in S protein can shape its conformational dynamics will contribute to the understanding of viral host tropism. Here using microsecond-scale multiple molecular dynamics simulations (MDS), we provide insights into the kinetic and thermodynamic contributions of these mutations to RBD opening pathways in S proteins of SARS-CoV-2 VOCs. Mutational effects were analyzed using atomistic (i) equilibrium MDS of closed and open states of S proteins and (ii) nonequilibrium MDS for closed-to-open transitions. In MDS of closed or open states, RBDs in S proteins of VOCs showed lower thermodynamic stability with higher kinetic fluctuations, compared to S proteins of ancestral SARS-CoV-2. For closed-to-open transitions in S proteins of VOCs, we observed apparently faster RBD opening with a 1.5-2-fold decrease in the thermodynamic free-energy barrier (ΔGclosedâopen). Saturation mutagenesis studies highlighted S protein mutations that may control its conformational dynamics and presentation to host receptors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
ACS Cent Sci
Year:
2023
Document type:
Article
Affiliation country:
United States