Distant residues modulate conformational opening in SARS-CoV-2 spike protein

Abstract

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the attachment of the receptor-binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, computational and experimental studies that search for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and preidentifying them can give clues for designing pan-coronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab initio from our model. Conversely, broad-spectrum therapeutics like drugs and monoclonal antibodies can target these key distant-but-conserved regions of the spike protein.

Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies: Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant

“…Multi-microsecond MD simulations of a 4.1 million atom system containing a patch of viral membrane with four full-length, fully glycosylated and palmitoylated S proteins allowed for a complete mapping of generic antibody binding signatures and characterization of the antibody and vaccine epitopes [84]. 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 [85][86][87][88][89][90][91]. Using data analysis and protein structure network modeling of MD simulations, residues that exhibit longdistance coupling with the RBD opening, including sites harboring functional mutations D614G and A570D, which points to the important role of the D614G variant in modulating allosteric communications in the S protein [87].…”

Glycan Masking of Epitopes in the NTD and RBD of the Spike Protein Elicits Broadly Neutralizing Antibodies Against SARS-CoV-2 Variants

“…One NTD neutralizing epitope has been shown to associate with the hydrophilic interactions of K147 and K150, the hydrophobic and/or π-π interactions of Y145 and W152, and the N -linked glycosylation site of N149 on the N3 loop of the NTD ( 34 ). It is also possible that the glycan-masking R158N/Y160T in the NTD interacts spatially with the RBD of another S1 monomer to affect the RBD up and down conformational structures ( 36 , 37 ). The C-type lectins such as L-SIGN and DC-SIGN have been shown to function as attachment receptors by enhancing ACE2-mediated infection, and monoclonal antibodies to NTD or the RBD conserved site can effectively block lectin-facilitated infection ( 38 ).…”

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

“…Computer simulations and protein modeling played an important role in shaping up our understanding of the dynamics and function of SARS-CoV-2 glycoproteins [46][47][48][49][50][51][52][53][54][55][56]. 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].…”

“…In particular, using an atomistic-based model of signal transmission in the SARS-CoV-2 S proteins, we determined that the D614G mutation can exert its effect through allosterically induced changes on stability and communications in the residue interaction networks [70,71]. Previous computational studies also identified residues that exhibit long-distance couplings with the RBD opening that included sites harboring functional mutations D614G and A570D shared across SARS-CoV-2 S protein variants [59]. The free-energy landscapes of the S protein derived from MD simulations, together with nudged elastic pathway optimization mapping of the RBD opening, revealed a specific transient allosteric pocket at the hinge region, which is located near D614 position, influences RBD dynamics [60].…”