RT Journal Article
SR Electronic
T1 Distant Residues Modulate the Conformational Opening in SARS-CoV-2 Spike Protein
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.07.415596
DO 10.1101/2020.12.07.415596
A1 Dhiman Ray
A1 Ly Le
A1 Ioan Andricioaei
YR 2020
UL http://biorxiv.org/content/early/2020/12/08/2020.12.07.415596.abstract
AB Infection of human cells by the novel coronavirus (SARS-Cov-2) involves the attachment of the receptor binding domain (RBD) of the spike protein to the peripheral membrane ACE2 receptors. The process is initiated by a down to up conformational change in the spike presenting the RBD to the receptor. Early stage computational and experimental studies on potential therapeutics have concentrated on the receptor binding domain, although this region is prone to mutations with the possibility of giving rise to widespread drug resistance. Here, using atomistic molecular dynamics simulation, we study the correlations between the RBD dynamics with physically distant residues in the spike protein, and provide a deeper understanding of their role in the infection, including the prediction of important mutations and of distant allosteric binding sites for therapeutics. Our model, based on time-independent component analysis (tICA) and protein graph connectivity network, was able to identify multiple residues, exhibiting long-distance coupling with the RBD opening dynamics. Mutation on these residues can lead to new strains of coronavirus with different degrees of infectivity and virulence. The most ubiquitous D614G mutation is predicted ab-initio from our model. Conversely, broad spectrum therapeutics like drugs and monoclonal antibodies can be generated targeting these key distant regions of the spike protein.Significance statement The novel coronavirus SARS-CoV-2 has created the biggest pandemic of 21st century resulting in significant economic and public health crisis. Significant research effort for drug design against COVID-19 is focused on the receptor binding domain of the spike protein, although this region is prone to mutations causing resistance against therapeutics. We applied time-independent component analysis (tICA) and protein connectivity network model, on all-atom molecular dynamics trajectories, to identify key non-RBD residues, playing crucial role in the conformational transition facilitating spike-receptor binding and infection of human cell. These residues can not only be targeted by broad spectrum antibodies and drugs, mutations in them can generate new strains of coronavirus resulting in future epidemic.Competing Interest StatementThe authors have declared no competing interest.