raw/papers/10.1101_2025.07.31.667969
biorxiv BIORXIV bioRxiv bioRxiv 2692-8205 Cold Spring Harbor Laboratory BIORXIV/2025/667969 10.1101/2025.07.31.667969 biorxiv;2025.07.31.667969v2 biorxiv;2025.07.31.667969 2025.07.31.667969 2025.07.31.667969 2025.07.31.667969 2.1 Regular Article New Results Biophysics How Well Do Molecular Dynamics Force Fields Model Peptides? A Systematic Benchmark Across Diverse Folding Behaviors 1 University of florida; 2 University of Florida * Corresponding author; email: [email protected] Singh Bhumika 1 Martinez-Noa Yisel 2 perez alberto 2 3 [email protected] 2026 2 8 2025 1 4 2026 2 8 2025 2025.07.31.667969 31 7 2025 31 3 2026 01 4 2026 © 2026, Posted by openRxiv 2026 This pre-print is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), CC BY-NC 4.0, as described at http://creativecommons.org/licenses/by-nc/4.0/ Linear peptides play essential roles in biology and drug discovery, frequently mediating protein-protein interactions through short, flexible motifs. However, their structural plasticity, ranging from disordered to context-dependent folding, makes them challenging targets for molecular simulations. In this work, we benchmark the performance of twelve popular and emerging fixed-charge force fields across a curated set of twelve peptides spanning structured miniproteins, context sensitive epitopes, and disordered sequences. Each peptide was simulated from both folded (200 ns) and extended (10 microseconds) states to assess stability, folding behavior, and force field biases. Our analysis reveals consistent trends: some force fields exhibit strong structural bias, others allow reversible fluctuations, and no single model performs optimally across all systems. The study highlights limitations in current force fields’ ability to balance disorder and secondary structure, particularly when modeling conformational selection. These results offer practical guidance for peptide modeling and establish a benchmark framework for future force field development and validation in peptide relevant regimes. National Institute of General Medical Sciences https://ror.org/04q48ey07 R01GM149646 citation_submitter_name alberto perez citation_submitter_email [email protected] citation_submitter_id 229408 citation_submitter_institution University of Florida special-property contains-inline-supplementary-material has-earlier-version yes Competing Interest Statement The authors have declared no competing interest. Summary of Updates: Incorporating new si figures and clarifications DC1 SI Figures