Comparative Study of Folded/Unfolded Peptide Dynamics with Modern AMBER Force Fields and Water Models

Abstract Molecular dynamics simulations of biomolecules depend fundamentally on the accuracy of the force field and its interplay with the solvent model. The AMBER family is the preeminent and most reliable force field for protein simulations, yet its performance can vary significantly with different water models. This study presents an unprecedented assessment of this coupling, evaluating 95 AMBER-water model combinations through 117.75 microseconds of simulation on four peptides with both structured and disordered conformations. While many pairings capably reproduce ordered secondary structures, our systematic analysis reveals which combinations also faithfully capture the structural features of intrinsically disordered regions. The ff15ipq force field with TIP4P-D water model emerges as a particularly accurate pairing, though several other combinations show significant promise. This comprehensive evaluation provides crucial guidance for selecting force fields that ensure high fidelity across diverse protein structural classes.