Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies : Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations

In this study, we used an integrative computational approach focused on comparative perturbation-based modeling to examine molecular mechanisms and determine functional signatures underlying role of functional residues in the SARS-CoV-2 spike protein that are targeted by novel mutational variants and antibody-escaping mutations. Atomistic simulations and functional dynamics analysis are combined with alanine scanning and mutational sensitivity profiling for the SARS-CoV-2 spike protein complexes with the ACE2 host receptor are REGN-COV2 antibody cocktail (REG10987+REG10933). Using alanine scanning and mutational sensitivity analysis, we have shown that K417, E484 and N501 residues correspond to key interacting centers with a significant degree of structural and energetic plasticity that allow mutants in these positions to afford the improved binding affinity with ACE2. Through perturbation-based network modeling and community analysis of the SARS-CoV-2 spike protein complexes with ACE2 we demonstrate that E406, N439, K417 and N501 residues serve as effector centers of allosteric interactions and anchor major inter-molecular communities that mediate long-range communication in the complexes. The results provide support to a model according to which mutational variants and antibody-escaping mutations constrained by the requirements for host receptor binding and preservation of stability may preferentially select structurally plastic and energetically adaptable allosteric centers to differentially modulate collective motions and allosteric interactions in the complexes with the ACE2 enzyme and REGN-COV2 antibody combination. This study suggests that SARS-CoV-2 spike protein may function as a versatile and functionally adaptable allosteric machine that exploits plasticity of allosteric regulatory centers to fine-tune response to antibody binding without compromising activity of the spike protein.