Drug Design in the Exascale Era: A Perspective from Massively Parallel QM/MM Simulations

The initial phases of drug discovery - in silico drug design - could benefit from first principle Quantum Mechanics / Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, yet many applications are currently limited by the short time scales that this approach can cover. Developing scalable first principle QM/MM MD interfaces fully exploiting current exascale machines - so far an unmet and crucial goal - will help overcome this problem, opening the way to the study of the thermodynamics and kinetics of ligand binding to protein with first principle accuracy. Here, taking two relevant case studies involving the interactions of ligands with rather large enzymes, we showcase the use of our recently developed massively scalable MiMiC QM/MM framework (currently using DFT to describe the QM region) to investigate reactions and ligand binding in enzymes of pharmacological relevance. We also demonstrate for the first time strong scaling of MiMiC QM/MM MD simulations with parallel efficiency above 70\% with over 40,000 cores. Thus, among many others, the MiMiC interface represents a promising candidate towards exascale applications by combining machine learning with statistical mechanics based algorithms tailored for exascale supercomputers.