The coronavirus disease 2019 (COVID-19) pandemic associated with the  severe acute respiratory syndrome (<i>SARS</i>) has been at the focal point of biomedical research. The structural and biochemical studies of the SARS-CoV-2 spike (S) glycoproteins and complexes with highly potent antibodies  have revealed  multiple conformation-dependent epitopes highlighting the link between conformational plasticity of  spike proteins and capacity for eliciting specific binding and broad neutralization responses.  We have developed an integrated computational  strategy that includes bioinformatics sequence and coevolutionary analysis,  atomistic biophysical  simulations and  perturbation-based network modeling of the SARS-CoV-2 spike  complexes with  antibodies targeting distinct  epitopes to  explore molecular mechanisms underlying  binding-induced  dynamics  and allosteric signaling in the SARS-CoV-2  spike  proteins.   This computational approach was used to examine molecular mechanisms underlying  functional  effects  of novel circulating   mutational variants  in the SARS-CoV-2 S protein. The results  of our studies  showed that circulating mutations    and  antibody-escaping mutations can target  allosteric hotspots  with sufficient dynamic plasticity and  evolutionary adaptability to   modulate binding with the host receptor, while  reducing efficiency of antibody recognition and  compromising the  long-range allosteric communications in the SARS-CoV-2  spike  proteins.  These critical functional sites on the spike protein  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 SARS-CoV-2 S protein may function as a functionally adaptable allosteric machine that exploits plasticity of allosteric  regulatory centers to  generate escape mutants that fine-tune response to antibody binding without compromising  activity of the spike protein. I will discuss  allosteric  regulatory mechanisms of SARS-CoV-2 S proteins and approaches for therapeutic intervention of the SARS-CoV-2  spike binding with the host receptor by targeting  hotspots of allosteric interactions and signal transmission in the SARS-CoV-2 proteins.

Conformational landscaping and mutational cartography of the SARS-COV-2 spike proteins: Probing mechanisms of antibody-induced neutralization and allosteric drug discovery

ACS Fall 2021

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