Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability

Abstract

Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of mutations with the enhanced virus infectivity and transmissibility. A detailed dynamic and energetic analysis of these variants was undertaken in the present work to quantify the effects of different mutations on functional conformational changes and stability of the SARS-CoV-2 spike protein. We employed the efficient and accurate coarse-grained (CG) simulations of multiple functional states of the D614G mutant, B.1.1.7 and B.1.351 spike variants to characterize conformational dynamics of the SARS-CoV-2 spike proteins and identify dynamic signatures of the functional regions that regulate transitions between the closed and open forms. By combining molecular simulations with full atomistic reconstruction of the trajectories and the ensemble-based mutational frustration analysis, we characterized how the intrinsic flexibility of specific spike regions can control functional conformational changes required for binding with the host-cell receptor. Using the residue-based mutational scanning of protein stability, we determined protein stability hotspots and identified potential energetic drivers favoring the receptor-accessible open spike states for the B.1.1.7 and B.1.351 spike variants. The results suggested that modulation of the energetic frustration at the inter-protomer interfaces can serve as a mechanism for allosteric couplings between mutational sites and the inter-protomer hinges of functional motions. The proposed mechanism of mutation-induced energetic frustration may result in greater adaptability and the emergence of multiple conformational states in the open form. This study suggested that SARS-CoV-2 B.1.1.7 and B.1.351 variants may leverage the intrinsic plasticity of functional regions in the spike protein for mutation-induced modulation of protein dynamics and allosteric regulation to control binding with the host cell receptor.

Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein

“…Such movements might favor ACE2 binding [ 31 ] by scanning the surrounding space for a possible alignment with the receptor, while indirectly exposing cryptic epitopes. [ 16 ] These findings, in context with the cryo‐EM results, [ 18,32 ] highlighted the importance of S2 flexibility, which plays a crucial role in conformational changes, [ 33 ] alignment, and membrane fusion process. [ 7,16 ] However, the limitations of the timescale in MD simulations restrict the exploration of long‐lasting contacts between the protein and the receptor, thus limiting our ability to characterize the interaction network that contributes to the binding process.…”

Is the Stalk of the SARS-CoV-2 Spike Protein Druggable?

“…For this reason, we excluded the terminal four N-terminal amino acids for the successive docking studies. Computational studies have suggested high flexibility of the SP stalk due to the presence of two unstructured knees 63 . Our simulations displayed similar behavior, where the bending of the stalk was aided by the opening of transitory pockets within the flexible loops, which temporarily moved away more than 20 Å from each other ( Figure 3B ) with an angle of about 133° between the alfa carbons of P1143-V1164-I1172 ( Figure S1) .…”

Bioinformatics study of selective inhibitor from <i>Garcinia mangostana</i> L. tackle HIV‑1 infection

“…Stability analysis of chemical bond interactions in ligand-protein interaction hot spots is performed through molecular dynamic simulation on the CABS-flex 2.0 server (http://biocomp.chem.uw.edu.pl/CABSflex2) [29]. This server identifies the stability of ligand-protein molecular complexes by calculating structural flexibility through large-scale conformational simulations.…”

“…This server identifies the stability of ligand-protein molecular complexes by calculating structural flexibility through large-scale conformational simulations. The output score of the simulation results is the root-mean-square fluctuation (RMSF) for the determination of molecular complex stability [29,30].…”