Mapping protein-ligand binding free energy contributions solely onto the ligand atoms

COMP 187

Sathesh Bhat, Enrico O. Purisima, enrico.purisima@nrc-cnrc.gc.ca, and Traian Sulea, traian.sulea@nrc-cnrc.gc.ca. Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montreal, QC H4P 2R2, Canada
Component analysis of binding free energies in the context of PB/GB calculations to estimate polar contributions to solvation is a non-perturbing alternative to computational alanine scanning, which partitions the total binding affinity into atomic contributions from both interacting molecules. However, splitting (equally) the binding affinity between partners can result in seemingly different conclusions from those of experimental mutational studies as to atomic/group contributions to binding. Here, employing a boundary element Poisson continuum electrostatic model calibrated with respect to solute dielectric and atomic radii on experimental protein-ligand binding affinities, we partition the total protein-ligand binding free energy only between the ligand atoms. A critical step in our decomposition is the assignment of the protein electrostatic desolvation to ligand atoms. Binding affinity distributions calculated over ligands are consistent with actual data for analog series. We can survey the ligand molecule for under-optimized energy components and locally improve them, as guided, for example, by charge optimization.