The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein

Abstract

Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-EM structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down to one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.

Atomistic Simulations and Network-Based Energetic Profiling of Binding and Allostery in the SARS-CoV-2 Spike Omicron BA.1, BA.1.1, BA.2 and BA.3 Subvariant Complexes with the Host Receptor: Revealing Hidden Functional Roles of the Binding Hotspots in Mediating Epistatic Effects and Long-Range Communication with Allosteric Pockets

“…Computer simulations provided important atomistic and mechanistic advances into understanding the dynamics and function of the SARS-CoV-2 S proteins [45-57]. All-atom MD simulations of the full-length SARS-CoV-2 S glycoprotein embedded in the viral membrane, with a complete glycosylation profile, were performed by Amaro and coworkers, providing an unprecedented level of detail about the conformational landscapes of the S proteins in the physiological environment [45].…”

“…MD simulations of the S-protein in solution and targeted simulations of conformational changes between the open and closed forms revealed the key electrostatic interdomain interactions mediating the protein stability and kinetics of the functional spike states [56]. Using the replica-exchange MD simulations with solute tempering of selected surface charged residues, the conformational landscapes of the full-length S protein trimers were investigated, unveiling previously unknown cryptic pockets and the meta-stable intermediate states [57]. A number of computational studies employed atomistic simulations and binding energy analysis to examine the interactions between the S-RBD Omicron and the ACE2 receptor [58-62].…”

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

“…A recent study by Dokainish et al. [ 52 ] described the opening of RBD by adopting the new generalized replica exchange method with solute tempering of selected surface charged residues (gREST_SSCR), an enhanced method derived from generalized replica exchange with solute tempering (gREST). [ 53 ] In this study, a selection of charged residues at the RBD interface was regarded as the solute region for gREST, exploring a range of temperatures while the solvent was kept at a constant temperature.…”

Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

“…Computer simulations provided important atomistic and mechanistic insights into understanding the dynamics and function of the SARS-CoV-2 glycoproteins. Molecular dynamics (MD) simulations of the SARS-CoV-2 S proteins and mutants detailed conformational changes and diversity of ensembles, demonstrating enhanced functional and structural plasticity of the S proteins [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. All-atom MD simulations of the full-length SARS-CoV-2 S glycoprotein embedded in the viral membrane, with a complete glycosylation profile, were performed by Amaro and coworkers, providing an unprecedented level of detail about the conformational landscapes of the S proteins in the physiological environment [ 57 ].…”

“…MD simulations of the S-protein in solution and targeted simulations of conformational changes between the open and closed forms revealed the key electrostatic interdomain interactions mediating the protein stability and kinetics of the functional spike states [ 64 ]. MD simulations characterized the conformational landscapes of the full-length S protein trimers detailing conformational transitions between functional states and unveiling previously unknown cryptic pockets [ 65 ]. Our studies revealed that the SARS-CoV-2 S protein can function as an allosteric regulatory machinery that can exploit the intrinsic plasticity of functional regions controlled by stable allosteric hotspots to modulate specific regulatory and binding functions [ 66 , 67 , 68 , 69 , 70 , 71 , 72 ].…”