Over the past two decades our group has established a rigorous statistical mechanical framework for the exploration of free energy landscapes associated with changes in the chemical constituency of molecules with a particular emphasis on biomolecules and their small molecule partners. These developments are relevant to the discovery and refinement of small molecules that bind in a targeted and specific manner to biological receptors (drug design and refinement), to modeling pH effects in biomolecules and in exploring the sequence space of viable proteins in folding, catalysis and protein-protein interactions. In this talk I will provide an overview of our λ-dynamics and multi-site λ-dynamics, which facilitate high-throughput free energy-based calculations of ligand binding affinities and protein stabilities and our constant pH molecular dynamics framework, which utilizes extended Lagrangian molecular dynamics to carry-out simulations of biological mixtures at constant chemical potential for protons (pH) and. These theoretical and methodological developments will be illustrated by recent applications to significant biological and biomedical questions.

Adventures in chemical space: Free energy landscapes for small molecule drug discovery, pH-mediated processes and protein design

ACS Spring 2022

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