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June 15, 2026Nature CommunicationsOpen Access

Convergence is not correctness: context-dependent performance of enhanced-sampling methods across biological complexity

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Authors

CKChristopher KangNorth Carolina State UniversityCCCheng Giuseppe ChenCentre National de la Recherche ScientifiqueCTChenyu TangCentre National de la Recherche Scientifique

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Implication

Randomized trial compares enhanced-sampling methods for biomolecular processes, indicating context-dependence in performance.

Key Points

  • This study aims to evaluate the performance of various enhanced-sampling methods in realistic biological contexts and reframe method selection as context-dependent.
  • Compared four enhanced-sampling approaches: REUS, WT-MtD, WTM-eABF, and OPES.
  • Analyzed performance across five biomolecular processes: ligand binding, conformational change, kinase activation, membrane permeation, and ion conduction.
  • Assessed method reliability using self-consistency metrics and cross-method validation against an independent reference.
  • Method performance varies significantly between different biological contexts.
  • Standard convergence metrics can yield misleading results, allowing incorrect free-energy profiles to appear valid.
  • Reliable free-energy estimation necessitates cross-method validation for informed decision-making.

Cite This Study

Kang et al. (2026) studied this question.

synapsesocial.com/papers/6a2f966ca1cfeec490827e1ahttps://doi.org/10.1038/s41467-026-74165-y
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