Massively Parallel Implementation of Steered Molecular Dynamics in Tinker-HP: Comparisons of Polarizable and Non-Polarizable Simulations of Realistic Systems.

Steered molecular dynamic (SMD) is a powerful technique able to accelerate rare event sampling in Molecular Dynamics (MD) simulations by applying an external force to a set of chosen atoms. Despite generating nonequilibrium simulations, SMD remains capable of reconstructing equilibrium properties such as the Potential of Mean Force (PMF). Of course, one would like to use all types of force fields (FF) ranging from classical ones to more advanced polarizable models using point induced dipoles and distributed multipoles such as AMOEBA. To enable such studies, the SMD methodology has been implemented in the framework of the massively parallel Tinker-HP software allowing for both long polarizable and non-polarizable MD simulations of large proteins. To validate this new implementation, we first compared the Tinker-HP SMD results to the literature. Tests have been performed on three different benchmark systems: the M-A deca-alanine (112 atoms), the ubiquitin (9737 atoms), and the CD2CD58 complex (97594 atoms). Non-polarizable (AMBER99, AMBER99SB, CHARMM22/CMAP, and OPLS-AA/L) and polarizable (AMOEBAPRO13 and AMOEBABIO18) force fields have been used. For each one of them, PMFs have been reconstructed and compared in terms of free energy barrier and hydrogen bonding fluctuations behavior over time. Using a SMD velocity of 0.01 Å/ps applied to a set of 20 trajectories, we show that polarizable and non-polarizable force fields do not always agree. As it could be anticipated, strong discrepancies are noticed between polarizable and non-polarizable models when considered in vacuum, whereas results are more comparable when a water environment is added. However, for the largest system, i.e., the CD2CD58 complex, strong differences related to the modeling of a salt bridge are noticed exhibiting some potential issues with classical FFs. Overall, such simulations highlight the importance of the inclusion of polarization effects as PMF free energy barriers computed with AMOEBA always decrease compared to non-polarizable force fields.