Dynamic Profiling of Binding and Allosteric Propensities of the SARS-CoV-2 Spike Protein with Different Classes of Antibodies: Mutational and Perturbation-Based Scanning Reveals the Allosteric Duality of Functionally Adaptable Hotspots

Abstract

The functional adaptability and conformational plasticity of SARS-CoV-2 spike proteins allow for the efficient modulation of complex phenotypic responses to the host receptor and antibodies. In this study, we combined atomistic simulations with mutational and perturbation-based scanning approaches to examine binding mechanisms of the SARS-CoV-2 spike proteins with three different classes of antibodies. The ensemble-based profiling of binding and allosteric propensities of the SARS-CoV-2 spike protein residues showed that these proteins can work as functionally adaptable and allosterically regulated machines. Conformational dynamics analysis revealed that binding-induced modulation of soft modes can elicit the unique protein response to different classes of antibodies. Mutational scanning heatmaps and sensitivity analysis revealed the binding energy hotspots for different classes of antibodies that are consistent with the experimental deep mutagenesis, showing that differences in the binding affinity caused by global circulating variants in spike positions K417, E484, and N501 are relatively moderate and may not fully account for the observed antibody resistance effects. Through functional dynamics analysis and perturbation-response scanning of the SARS-CoV-2 spike protein residues in the unbound form and antibody-bound forms, we examine how antibody binding can modulate allosteric propensities of spike protein residues and determine allosteric hotspots that control signal transmission and global conformational changes. These results show that residues K417, E484, and N501 targeted by circulating mutations correspond to a group of versatile allosteric centers in which small perturbations can modulate collective motions, alter the global allosteric response, and elicit binding resistance. We suggest that the SARS-CoV-2 S protein may exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter the response to antibody binding without compromising the activity of the spike protein.

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

“…The latest extensive molecular dynamics (MD) simulations and free-energy landscape mapping studies of the SARS-CoV-2 S proteins and mutants detailed conformational changes and diversity of ensembles, further supporting the notion of enhanced functional and structural plasticity of S proteins [57][58][59][60][61][62][63]. Our recent studies offered evidence that the SARS-CoV-2 spike protein can function as an allosterically regulated machine that exploits plasticity of allosteric hotspots to fine-tune response to antibody binding [64][65][66][67][68][69]. These studies showed that examining allosteric behavior of the SARS-CoV-2 S proteins may be useful to uncover functional mechanisms and rationalize the growing body of diverse experimental data.…”

Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants

“…In a recent study of dynamic profiling of binding and allosteric propensities of the SARS-CoV-2 spike protein with different classes of antibodies, it was seen that RBD mutation sites K417, E484, and N501 correspond to a group of versatile allosteric centers in which small perturbations can modulate collective motions, alter the global allosteric response, and elicit binding resistance. 49 …”

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

“…The copyright holder for this preprint (which this version posted July 8, 2021. ; https://doi.org/10.1101/2021.07.07.451538 doi: bioRxiv preprint 8 MD simulations with coevolutionary analysis and network modeling to present evidence that the SARS-CoV-2 spike protein function as allosterically regulated machine that exploits plasticity of allosteric hotspots to fine-tune response to antibody binding. [77][78][79][80][81][82] These studies showed that examining allosteric behavior of the SARS-CoV-2 pike proteins may be useful to uncover functional mechanisms and rationalize the growing body of diverse experimental data.…”

“…71 Our recent studies combined coarse-grained and atomistic MD simulations with coevolutionary analysis and network modeling to present evidence that the SARS-CoV-2 spike protein function as allosterically regulated machine that exploits plasticity of allosteric hotspots to fine-tune response to antibody binding. 77–82 These studies showed that examining allosteric behavior of the SARS-CoV-2 pike proteins may be useful to uncover functional mechanisms and rationalize the growing body of diverse experimental data. A critical review of computational simulation studies of the SARS-CoV-2 S proteins highlighted the synergies between experiments and simulations, outlining directions for computational biology research in understanding mechanisms of COVID-19 protein targets.…”