Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

Abstract

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus–host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein–protein interfaces responsible for virus entry and infection transmission.

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

“… 60 , 61 Our recent study examined the molecular basis of the SARS-CoV-2 binding with the ACE2 enzyme through the lens of coevolution and conformational dynamics that conspire to drive cooperative binding interactions and signal transmission. 62 Using protein contact networks and perturbation response scanning based on elastic network models, we recently presented an integrated approach for detecting allosteric sites on the SARS-CoV- 2 spike protein, showing convergence to a single allosteric region. 63 Molecular simulations and network modeling approaches were also used on our most recent investigation to present evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states.…”

Coevolutionary Analysis and Perturbation-Based Network Modeling of the SARS-CoV-2 Spike Protein Complexes with Antibodies: Binding-Induced Control of Dynamics, Allosteric Interactions and Signaling

“…51 MD simulations of the SARS-CoV-2 spike glycoprotein identified differences in flexibility of functional regions that may be important for modulating the equilibrium changes and binding to ACE2 host receptor. 52 Computational studies examined SARS-CoV-2 S trimer interactions with ACE2 enzyme using the recent crystal structures [53][54][55][56][57][58][59][60][61][62] providing insights into the key determinants of the binding affinity and selectivity. A comprehensive study employed MD simulations to reveal a balance of hydrophobic interactions and elaborate hydrogen-bonding network in the SARS-CoV-2-RBD interface.…”

“…59 Molecular mechanisms of the SARS-CoV-2 binding with ACE2 enzyme were analyzed in our recent study using coevolution and conformational dynamics. 62 Using protein contact networks and perturbation response scanning based on elastic network models, we recently discovered existence of allosteric sites on the SARS-CoV-2 spike protein. 63 By using molecular simulations and network modeling we recently presented the first evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states.…”

Computational Analysis of Protein Stability and Allosteric Interaction Networks in Distinct Conformational Forms of the SARS-CoV-2 Spike D614G Mutant: Reconciling Functional Mechanisms through Allosteric Model of Spike Regulation

“…55 Computational modeling and MD simulations have been instrumental in predicting dynamics and function of SARS-CoV-2 glycoproteins. [56][57][58][59][60][61][62][63][64] Our recent study examined molecular basis of the SARS-CoV-2 binding with ACE2 enzyme showing that coevolution and conformational dynamics conspire to drive cooperative binding interactions and signal transmission. 62 Using protein contact networks and perturbation response scanning allosteric sites on the SARS-CoV-2 spike protein were proposed.…”

“…[56][57][58][59][60][61][62][63][64] Our recent study examined molecular basis of the SARS-CoV-2 binding with ACE2 enzyme showing that coevolution and conformational dynamics conspire to drive cooperative binding interactions and signal transmission. 62 Using protein contact networks and perturbation response scanning allosteric sites on the SARS-CoV-2 spike protein were proposed. 63 Molecular simulations and network modeling approaches were used on our most recent investigation to present evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states.…”