Recent years have witnessed drastic improvement in general-purpose explicit solvent protein force fields, partially driven by the need to study intrinsically disordered proteins (IDPs). Yet, the state-of-the-art force fields such as CHARMM36m (c36m) and a99SB-disp still provide different performance in simulating disordered proteins, where c36m still has a strong bias towards over-compaction for larger IDPs. Here, we systematically examine the stabilities of pair-wise protein-protein interactions in c36m and a99SB-disp. For this, we selected a set of 46 amino acid backbone and side chain pairs in representative configurations and calculated the free energy profiles of their interactions. The results show that the c36m systematically predicts stronger protein-protein interactions compared to a99SB-disp, by an average of 0.2 kcal/mol for nonpolar pairs, 0.6 kcal/mol for polar pairs and 0.8 kcal/mol for salt-bridges. Strikingly, the most severe overstabilization in c36m is observed for charged pairs involving the Arg and Glu side chains, by up to 2.9 kcal/mol. Importantly, the system overstabilization of c36m is only marginally alleviated by the previously proposed ad hoc patch to c36m, named c36mw, that increases the dispersion interactions between TIP3P hydrogens and protein atoms. Further free energy decomposition suggested that the over-stabilization in c36m should be mainly attributed to protein-water interactions, particularly the electrostatic component.  This work not only provides a set of useful systems for the benchmarking and optimization of protein force fields, but also suggests that the electrostatic interactions could be carefully rebalanced in further optimization of c36m.

Likely over-stabilization of charge-charge interactions in CHARMM36m(w)

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