Systematic Validation of Protein Force Fields against Experimental Data

TLDR

Molecular dynamics simulations model the structures, motions, and interactions of biological macromolecules, but their accuracy hinges on the underlying force field. This study systematically evaluates eight protein force fields by comparing their predictions with experimental data from long‑timescale simulations. The authors benchmarked the force fields against experimental NMR data for folded proteins, assessed secondary‑structure biases using helical and sheet‑rich peptides, and tested folding of two small proteins—one α‑helical and one β‑sheet. Results indicate that force fields have improved over time, with the latest versions providing an accurate description of many structural and dynamical properties, though some imperfections remain.

Abstract

Molecular dynamics simulations provide a vehicle for capturing the structures, motions, and interactions of biological macromolecules in full atomic detail. The accuracy of such simulations, however, is critically dependent on the force field--the mathematical model used to approximate the atomic-level forces acting on the simulated molecular system. Here we present a systematic and extensive evaluation of eight different protein force fields based on comparisons of experimental data with molecular dynamics simulations that reach a previously inaccessible timescale. First, through extensive comparisons with experimental NMR data, we examined the force fields' abilities to describe the structure and fluctuations of folded proteins. Second, we quantified potential biases towards different secondary structure types by comparing experimental and simulation data for small peptides that preferentially populate either helical or sheet-like structures. Third, we tested the force fields' abilities to fold two small proteins--one α-helical, the other with β-sheet structure. The results suggest that force fields have improved over time, and that the most recent versions, while not perfect, provide an accurate description of many structural and dynamical properties of proteins.