Simulation studies of polypeptoids using replica exchange with dynamical scaling and dihedral biasing.

Polypeptoids differ from polypeptides in that the amide bond can more frequently adopt both cis and trans conformations. The transition between the two conformations requires overcoming a large energy barrier, making it difficult for conventional molecular simulations to adequately visit the cis and trans structures. A replica-exchange method is presented that allows for easy rotations of the amide bond and also an efficient linking to a high temperature replica. The method allows for just three replicas (one at the temperature and Hamiltonian of interest, a second high temperature replica with a biased dihedral potential, and a third connecting them) to overcome the amide bond sampling problem and also enhance sampling for other coordinates. The results indicate that for short peptoid oligomers, the conformations can range from all cis to all trans with an average cis/trans ratio that depends on side chain and potential model.

Molecular dynamics simulations of the flexibility and inhibition of SARS-CoV-2 NSP 13 helicase.

The helicase protein of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is both a good potential drug target and very flexible. The flexibility, and therefore its function, could be reduced through knowledge of these motions and identification of allosteric pockets. Using molecular dynamics simulations with enhanced sampling, we determined key modes of motion and sites on the protein that are at the interface between flexible domains of the proteins. We developed an approach to map the principal components of motion onto the surface of a potential binding pocket to help in the identification of allosteric sites.

Molecular dynamics simulations of allosteric motions and competitive inhibition of the Zika virus helicase.

The 2015 Zika outbreak sparked major global concern and emphasized the reality and dangers still posed by mosquito borne pathogens. While efforts have been made to develop a vaccine and other therapeutics, there is still a great demand for antiviral drugs targeting Zika and other flaviviruses. The non-structural protein 3 (NS3) helicase is a vital component of the viral replication complex, tasked with unwinding the viral dsRNA molecule into single strands. Given this critical function, the Zika virus helicase is a potential therapeutic target and the focus of many ongoing research efforts. Using a combination of drug docking and molecular dynamics simulations, we have identified a list of competitive helicase inhibitors targeting the ATP hydrolysis site and have discovered a potential allosteric site capable of distorting both of the protein's active sites.