NepoIP/MM: Toward Accurate Biomolecular Simulation with a Machine Learning/Molecular Mechanics Model Incorporating Polarization Effects.

Machine learning force fields offer the ability to simulate biomolecules with quantum mechanical accuracy while significantly reducing computational costs, attracting a growing amount of attention in biophysics. Meanwhile, by leveraging the efficiency of molecular mechanics in modeling solvent molecules and long-range interactions, a hybrid machine learning/molecular mechanics (ML/MM) model offers a more realistic approach to describing complex biomolecular systems in solution. However, multiscale models with electrostatic embedding require accounting for the polarization of the ML region induced by the MM environment. To address this, we adapt the state-of-the-art NequIP architecture into a polarizable ML force field, NepoIP, enabling the modeling of polarization effects based on the external electrostatic potential. We found that the nanosecond MD simulations based on NepoIP/MM are stable for the periodic solvated dipeptide system, and the converged sampling shows excellent agreement with the reference QM/MM level. Moreover, we show that a single NepoIP model can be transferable across different MM force fields, as well as an extremely different MM environment of water and proteins, laying the foundation for developing a general ML biomolecular force field to be used in ML/MM with electrostatic embedding.