Abstract
Multivalent ions bind to proteins to control many biological processes. Molecular simulations can effectively supplement experiments to resolve underlying mechanisms, but suffer from reliability and feasibility issues in describing ion-protein binding in the condensed phase. Here we present a molecular mechanics based generalizable solution to this long-standing challenge. Using the divalent Mg
2+
as a model, we demonstrate that our approach yields unprecedented accuracy in describing its binding to proteins in solution – compared to high level quantum mechanics, the mean error in local interaction energies is 0.5%, and the binding modes and binding free energies match experiment. Our study also shows that key to achieving this accuracy requires a delicate balance between the large repulsive and attractive forces at short distances near ions for which explicit modeling of polarization is essential. Overall, our work lays foundation for future development of molecular simulation methods for ions and opens the way to quantitatively study Mg-dependent mechanisms in hundreds of enzymes and proteins.