Improving the CHARMM36m force field for arginine-phosphate interactions.

Abstract

Noncovalent binding interactions between arginine and phosphate, such as the anchoring of transmembrane helices to phospholipid membrane interfaces or the binding of SH2 domain proteins with phosphorylated peptides, are essential for structural integrity or signal recognition in many biological processes. Using 120 ns long MD simulations, we find that arginine and phosphate have multiple binding conformations. The binding conformations are clustered into five groups and we compute binding energies for these clusters. Free energy perturbation (FEP) calculations are used to estimate the binding free energy using the current CHARMM36m and its CUFIX corrected version. Umbrella sampling (US) is used to generate the potential of mean force (PMF) along the inter-group distance reaction coordinate. Our results were compared with data from isothermal calorimetry (ITC) and suggest that neither the CHARMM36m nor the CUFIX-correct version match experiment and the ITC value is in between these force field estimates. Our current work focuses on the generation of improved force field parameters for arginine-phosphate interactions and experimental validation of these parameters for peptide-liposome binding.