Improved Modeling of Cation‐π and Anion‐Ring Interactions Using the Drude Polarizable Empirical Force Field for Proteins

Cation-pi interactions are noncovalent interactions between a pi-electron system and a positively charged ion that are regarded as a strong noncovalent interaction and are ubiquitous in biological systems. Similarly, though less studied, anion-ring interactions are present in proteins along with in-plane interactions of anions with aromatic rings. As these interactions are between a polarizing ion and a polarizable pi system, the accuracy of the treatment of these interactions in molecular dynamics (MD) simulations using additive force fields (FFs) may be limited. In the present work, to allow for a better description of ion-pi interactions in proteins in the Drude-2013 protein polarizable FF, we systematically optimized the parameters for these interactions targeting model compound quantum mechanical (QM) interaction energies with atom pair-specific Lennard-Jones parameters along with virtual particles as selected ring centroids introduced to target the QM interaction energies and geometries. Subsequently, MD simulations were performed on a series of protein structures where ion-pi pairs occur to evaluate the optimized parameters in the context of the Drude-2013 FF. The resulting FF leads to a significant improvement in reproducing the ion-pi pair distances observed in experimental protein structures, as well as a smaller root-mean-square differences and fluctuations of the overall protein structures from experimental structures. Accordingly, the optimized Drude-2013 protein polarizable FF is suggested for use in MD simulations of proteins where cation-pi and anion-ring interactions are critical. (c) 2019 Wiley Periodicals, Inc.