Optimized Molecular Dynamics Force Fields Applied to the Helix−Coil Transition of Polypeptides

TLDR

Obtaining the correct balance of secondary structure propensities is a central priority in protein force‑field development, and current force fields differ significantly in their α‑helical propensities, making a correction to match experimental results highly desirable. The study aims to correct force fields to reproduce experimental helix fractions in short peptides and to analyze the physical origins of remaining shortcomings to guide future force‑field development. The optimized force fields reproduce the experimental helix fraction at 300 K and agree with NMR data for proteins and peptides not used in training, yet they underestimate the temperature dependence of helix content, with both enthalpic and entropic contributions to helix formation about half the experimental values.

Abstract

Obtaining the correct balance of secondary structure propensities is a central priority in protein force-field development. Given that current force fields differ significantly in their α-helical propensities, a correction to match experimental results would be highly desirable. We have determined simple backbone energy corrections for two force fields to reproduce the fraction of helix measured in short peptides at 300 K. As validation, we show that the optimized force fields produce results in excellent agreement with nuclear magnetic resonance experiments for folded proteins and short peptides not used in the optimization. However, despite the agreement at ambient conditions, the dependence of the helix content on temperature is too weak, a problem shared with other force fields. A fit of the Lifson−Roig helix−coil theory shows that both the enthalpy and entropy of helix formation are too small: the helix extension parameter w agrees well with experiment, but its entropic and enthalpic components are both only about half the respective experimental estimates. Our structural and thermodynamic analyses point toward the physical origins of these shortcomings in current force fields, and suggest ways to address them in future force-field development.