Project 1. Infrastructure for Accurate and Efficient Binding Affinity Calculations

Our goal is methods for predicting binding strengths, or binding free energies, between biomolecules. Accurate, reliable simulation-based tools for affinity predictions would transform the process of pharmaceutical drug discovery and enable new kinds of science. Recently, a tool called alchemical free energy calculations has shown considerable promise for predicting binding free energies from simulations. Several studies suggest these calculations could now be useful in practice in drug discovery and other applications, but for the difficulty of setting them up [1,2]. We propose to further develop a pipeline to set up molecular dynamics simulations and associated alchemical free energy calculations, which will make it possible for these calculations to be more routine, and done with less expert intervention. We will implement tools to automate steps that now require expert intervention, removing the bottleneck and allowing widespread application of these tools using LONI computational resources. The pipeline will take an arbitrary protein of interest, begin with a protein data bank structure of the protein, assign reasonable protonation states to residues, including titratable residues, then build in missing loops and residues – those which may not be resolved in crystal structures. Another componen