Nearest-Neighbor Effects in Short Unfolded Peptides: An Assessment of Molecular Dynamics Force Fields.

Molecular dynamics (MD) is a unique tool for the investigation of intrinsically disordered proteins (IDPs); however, the reliability of MD predictions depends on the accuracy of the underlying force field. Here, we evaluate CHARMM36m, Amber ff14SB, and Amber ff24EXP-GA with respect to their capacity to capture experimentally observed nearest-neighbor (NN) effects on the conformational dynamics of amino acid residues in short unfolded peptides in water. Amber ff24EXP-GA, developed from the parent Amber ff14SB, which is more amino acid-specific than the other two force fields and reproduces intrinsic conformational ensembles of amino acid residues significantly better than the parent force field, captures the NN effects better than Amber ff14SB. Despite a lack of residue specificity in intrinsic conformational ensembles, CHARMM36m, calibrated on global properties of IDPs, reproduces the NN effects on par with Amber ff24EXP-GA. These findings are important for the development of next-generation force fields that reproduce both the residue-specific conformational dynamics and global properties of IDPs.