Abstract:
Computational methods for predicting the binding affinity of small organic molecules to biological macromolecules cover a vast range of theoretical and physical complexity. Generally, as the required accuracy increases so does the computational cost, thereby making the user choose a method that suits their needs within the parameters of the project. We present how WScore, a rigid-receptor docking program normally consigned to structure-based hit discovery in drug design projects, is systematically ameliorated to perform accurately enough for lead optimization with a set of ROCK1 complexes and congeneric ligands from a structure-activity relationship study. Initial WScore results from the Schrödinger 2019-3 release show poor correlation (R^2 ~0.0), large errors in predicted binding affinity (RMSE = 2.30 kcal/mol), and bad native pose prediction (two RMSD >4Å) for the six ROCK1 crystal structures and associated active congeneric ligands. Improvements to WScore’s treatment of desolvation, myriad code fixes, and a simple ensemble consensus scoring protocol improved the correlation (R^2 = 0.613), the predicted affinity accuracy (RMSE = 1.34 kcal/mol), and native pose prediction (one RMSD >1.5Å). Then we evaluate a physically and thermodynamically rigorous free energy perturbation (FEP) method, FEP+, against CryoEM structures of the Machilis hrabei olfactory receptor, MhOR5, and associated dose-response assays of a panel of small molecules. Augmented with an induced-fit docking method, IFD-MD, FEP+ performs well for ligand relative binding FEP (RBFEP) calculations which correlate with experimental log(EC50) with an R^2 = 0.551. Ligand absolute binding FEP (ABFEP) on a set of disparate ligands from the MhOR5 panel has poor correlation (R^2 = 0.106) for ligands with log(EC50) within the assay range. But qualitative predictions correctly identify the ligands with the lowest potency. Protein mutation calculations have no log(EC50) correlation and consistently fail to predict the loss of potency for a majority of MhOR5 single point mutations. We believe that structural insights of the mutants for both bound and unbound (apo) states are required to better understand the shortcomings of the current FEP+ methods for protein mutation RBFEP. Finally, improvements to GPU-accelarated linear algebra functions in an Auxiliary-Field Quantum Monte Carlo (AFQMC) program effect an average 50-fold reduction in GPU compute time using optimized GPU library routines instead of custom made GPU kernels. Also MPI parallelization of the population control algorithm that destroys low-weight walkers has a bottleneck removed in large, multi-node AFQMC calculations.
