Significance The novel coronavirus (SARS-CoV-2) pandemic resulted in the largest public health crisis in recent times. Significant drug design effort against SARS-CoV-2 is focused on the receptor-binding domain (RBD) of the spike protein, although this region is highly prone to mutations causing therapeutic resistance. We applied deep data analysis methods on all-atom molecular dynamics simulations to identify key non-RBD residues that play a crucial role in spike−receptor binding and infection. Because the non-RBD residues are typically conserved across multiple coronaviruses, they can be targeted by broad-spectrum antibodies and drugs to treat infections from new strains that might appear during future epidemics. 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.
【저자키워드】 COVID-19, molecular dynamics, molecular biophysics, virus structure, statistical mechanics, 【초록키워드】 SARS-CoV-2, Vaccine, coronavirus, pandemic, Mutation, drug design, antibody, Therapeutics, monoclonal antibody, mutations, SARS-CoV-2 variant, Infection, Epidemics, ACE2 receptor, drug, molecular dynamics, public health crisis, severe acute respiratory syndrome Coronavirus, monoclonal antibodies, Spike protein, Health crisis, Molecular dynamics simulation, Novel coronavirus, Protein, Outbreaks, Region, D614G mutation, Receptor-binding domain, Transmissibility, RBD, therapeutic, Data analysis, ACE2 receptors, membrane, drug resistance, mutant, receptor, molecular, respiratory, correlation, virulence, binding, Analysis, Spike proteins, conformational change, host cells, focus, acute respiratory syndrome, independent component analysis, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, residue, attachment, effort, correlations, new strain, treat, residues, RBD region, contagious, multiple coronaviruses, hotspot, A570D, all-atom molecular dynamics simulations, implication, event, independent, predicted, identify, conserved, involved, applied, the spike protein, the RBD, the receptor-binding domain, initiated, Significant, Significance, 【제목키워드】 SARS-CoV-2 spike protein, residue, modulate, conformational, Distant,