Long-time-step molecular dynamics can retard simulation of protein-ligand recognition process

Molecular dynamics (MD) simulation of biologically relevant processes at realistic time scale and atomistic precision is generally limited by prohibitively large computational cost, due to its restriction of using an ultrashort integration time step (1-2 fs). A popular numerical recipe to reduce the associated computational burden is adopting schemes that would allow relatively longer-time-step for MD propagation. Here, we explore the perceived potential of one of the most frequently used long-time-step protocols, namely the hydrogen mass repartitioning (HMR) approach, in alleviating the computational overhead associated with simulation of the kinetic process of protein-ligand recognition events. By repartitioning the mass of heavier atoms to their linked hydrogen atoms, HMR leverages around twofold longer time step than regular simulation, holding promise of significant performance boost. However, our probe into direct simulation of the protein-ligand recognition event, one of the computationally most challenging processes, shows that long-time-step HMR MD simulations do not necessarily translate to a computationally affordable solution. Our investigations spanning cumulative 176 ms in three independent proteins (T4 lyso-zyme, sensor domain of MopR, and galectin-3) show that long-time-step HMR-based MD simulations can catch the ligand in its act of recognizing the native cavity. But, as a major caveat, the ligand is found to require significantly longer time to identify buried native protein cavity in an HMR MD simulation than regular simulation, thereby defeating the purpose of its usage for performance upgrade. A molecular analysis shows that the longer time required by a ligand to recognize the protein in HMR is rooted in faster diffusion of the ligand, which reduces the survival probability of decisive on-pathway metastable intermediates, thereby slowing down the eventual recognition process at the native cavity. Together, the investigation stresses careful assess-ment of pitfalls of long-time-step algorithms before attempting to utilize them for higher performance for biomolecular recognition simulations.

Automated summary

Molecular dynamics (MD) simulations of biologically relevant processes are limited by computational cost. The hydrogen mass repartitioning (HMR) approach allows longer time step for simulation, but it does not necessarily improve the performance of protein-ligand recognition simulations.