Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Tuesday Speaker Abstracts

CLOUD-ENABLED DYNAMICAL NONEQUILIBRIUM MOLECULAR DYNAMICS SIMULATIONS REVEAL THE STRUCTURAL BASIS FOR ALLOSTERY, SIGNAL PROPAGATION AND NETWORKS INVOLVED IN EVOLUTION OF CATALYTIC ACTIVITY Adrian J. Mulholland 1 ; 1 University of Bristol, School of Chemistry, Bristol, United Kingdom Simulations have helped to identify important features of SARS-CoV-2 proteins, such as the effects of linoleic acid on the viral Spike protein. Dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations reveal allosteric coupling of the fatty acid binding site to distant functional regions in the Spike, such as the furin cleavage site. They also show significant differences between viral variants (Alpha, Delta and Omicron). They have identified coupling between allosteric sites and the active site in beta-lactamase enzymes; the pathways identified contain positions that differ between clinically relevant variants, indicating that allosteric effects modulate the spectrum of activity. The D-NEMD approach can effectively combine cloud-based and other HPC resources. Increasingly, simulations are contributing to the engineering of natural enzymes and de novo biocatalysts. Simulations are also contributing to the emerging evidence that activation heat capacity is an important factor in enzyme evolution and thermoadaptation. Directed evolution of a designed Kemp eliminase unexpectedly introduced curvature into the temperature dependence of reaction, showing the emergence of an activation heat capacity. The dynamical networks involved provide targets for mutation. QM/MM methods can identify mechanisms of reaction (e.g. for covalent inhibitors such as ibrutinib, and for the SARS-CoV-2 main protease, Mpro) determinants of catalytic activity and predict the activity of bacterial enzymes against antibiotics. Virtual reality offers new ways interact with simulations, and new ways to collaborate. Interactive MD simulation in virtual reality (iMD-VR) allows fully flexible docking of drugs into protein targets. The COVID-19 pandemic has highlighted the need for effective tools for virtual collaboration. Groups of researchers can work together, using iMD-VR for molecular problems such as structure-based drug design. Using the cloud, researchers in different physical locations can work together in the same virtual molecular environment. Simulations, including iMD-VR, with sharing of models, have been used to design peptide inhibitors of the SARS-CoV-2 Mpro.

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