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| Main Authors: | , , |
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| Format: | Preprint |
| Published: |
2026
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| Subjects: | |
| Online Access: | https://arxiv.org/abs/2602.19936 |
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Table of Contents:
- While recent advances in AI have transformed protein structure prediction, protein function is also strongly influenced by the thermodynamic and kinetic features encoded in its underlying free-energy surface. Here, we propose a data-efficient framework for engineering protein conformational kinetics by rationally reshaping free-energy landscapes to control transition rates. Built on the Collective Variables for Free Energy Surface Tailoring (CV-FEST) framework, the approach is validated on point mutations of the miniprotein Chignolin. The framework relies on Harmonic Linear Discriminant Analysis (HLDA)-based collective variables (CVs) constructed from short molecular dynamics trajectories confined to metastable folded and unfolded basins, requiring only limited local sampling rather than exhaustive rare-event simulations. Notably, the HLDA CV derived solely from the wild-type system provides residue-level scores that predict whether mutations at specific positions are likely to accelerate or slow unfolding transitions. Furthermore, the leading HLDA eigenvalue associated with the derived CV, a quantitative measure of the one-dimensional statistical separation between folded and unfolded ensembles, is significantly correlated with transition rates across mutations. Together, these results suggest that mutation-dependent kinetic effects can be inferred from minimal in-basin sampling, providing a practical route for guiding peptide and protein engineering through collective-variable design, free-energy surface engineering, and data-efficient molecular simulation.