Abstract
The recently emerged SARS-like coronavirus (SARS-CoV-2) has continued to spread rapidly among humans with alarming upsurges in global mortality rates. A major key to tackling this virus is to disrupt its RNA replication process as previously reported for Remdesivir (Rem-P 3 ). In this study, we theorize, using computational simulations, novel mechanisms that may underlie the binding of Rem-P 3 to SARS-CoV-2 RdRp-NSPs complex; a multimeric assembly that drives viral RNA replication in human hosts. Findings revealed that while ATP-binding stabilized the replicative tripartite, Rem-P 3 disintegrated the RdRp-NSP complex, starting with the detachment of the NSP7-NSP8 heterodimer followed by minimal displacement of the second NSP8 subunit (NSP8 II ). More so, Rem-P 3 interacted with a relatively higher affinity (ΔG bind ) while inducing high perturbations across the RdRp-NSP domains. D452, T556, V557, S682, and D760 were identified for their crucial roles in stacking the cyano-adenosine and 3,4-dihydroxyoxolan rings of Rem-P 3 while its flexible P 3 tail extended towards the palm domain blocking D618 and K798; a residue-pair identified for essential roles in RNA replication. However, ATP folded away from D618 indicative of a more coordinated binding favorable for nucleotide polymerization. We believe findings from this study will significantly contribute to the structure-based design of novel disruptors of the SARS-CoV-2 RNA replicative machinery.
Keywords: ATP; Accelerated molecular dynamics simulation; Non-structural proteins; RNA-dependent RNA polymerase; Remdesivir; SARS-CoV-2.
【저자키워드】 SARS-CoV-2, Remdesivir, non-structural proteins, RNA-dependent RNA polymerase, ATP, Accelerated molecular dynamics simulation, 【초록키워드】 SARS-CoV-2, Human, Remdesivir, molecular dynamics, virus, non-structural proteins, Molecular dynamics simulation, RNA, Replication, Spread, RdRP, RNA-dependent RNA polymerase, Viral RNA, Nsp7, structure-based design, molecular, NSP8, mechanism, adenosine, binding, nucleotide, Perturbation, followed by, subunit, domains, complex, domain, hosts, finding, higher affinity, Detachment, SARS-like coronavirus, PALM, flexible, computational simulations, significantly, reported, contribute, replicative, disrupt, underlie, global mortality, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, Remdesivir, complex, piece,