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

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... 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.