Guest Speaker Prof. Martin McCullagh, Oklahoma State University

Title: Molecular Simulations Reveal that Motif V is a Throttle for the ATP-dependent Translocation Mechanisms of two Viral Helicases

Helicases of positive sense RNA viruses, such as SARS-CoV-2 and dengue, utilize the chemical energy from ATP binding, hydrolysis, and product release to translocate along viral RNA, a critical component of the viral RNA replication cycle. The allosteric coupling between the ATP pocket and RNA cleft represents a novel target for the development of specific inhibitors but the characterization of these mechanisms remains a challenge for any single technique. We use a combination of quantum chemical calculations, extensive all-atom molecular dynamics simulations, and in-house developed allosteric analyses to characterize the translocation mechanism of dengue virus NS3 helicase. Our results highlight Motif V as particularly important for the coupling of the two pockets. In collaboration with the Geiss group at Colorado State University, targeted mutagenesis of Motif V was found to enhance certain helicase activity of dengue NS3 suggesting that Motif V actually throttles helicase activity. Intriguingly, we have recently identified Motif V as a critical component of the allosteric mechanism in SARS-CoV2 nsp13 helicase using a similar suite of simulations and analyses. Taken together, these results suggest that Motif V throttles the ATP-dependent activity of viral helicases and is an interesting target for antiviral development.