Keywords

protein engineering, Alphafold3, ensemble, PCA, molecular dynamics

Abstract

Protein function emerges from dynamic conformational changes, yet structure prediction methods provide only static snapshots. While AlphaFold3 (AF3) predicts protein structures, the potential for extracting dynamic information from its ensemble predictions has remained underexplored. Here, we demonstrate that AF3 structural ensembles contain substantial dynamic information that correlates remarkably well with molecular dynamics simulations (MD). We developed ChronoSort, a novel algorithm that organizes static structure predictions into temporally coherent trajectories by minimizing structural differences between neighboring frames. Through systematic analysis of four diverse protein targets, we show that root-mean-square fluctuations derived from AF3 ensembles can correlate strongly with those from MD (r = 0.53 to 0.84). Principal component analysis reveals that AF3 predictions capture the same collective motion patterns observed in molecular dynamics trajectories, with eigenvector similarities significantly exceeding random distributions. ChronoSort trajectories exhibit structural evolution profiles comparable to MD. These findings suggest that modern AI-based structure prediction tools encode conformational flexibility information that can be systematically extracted without expensive MD. We provide ChronoSort as open-source software to enable broad community adoption. This work offers a novel approach to extracting functional insights from structure prediction tools in minutes, with significant implications for synthetic biology, protein engineering, drug discovery, and structure–function studies.

Original Publication Citation

Argyle, M. J., Heaps, W. P., Kubalek, C., Gardiner, S. S., Bundy, B. C., & Della Corte, D. (2025). ChronoSort: Revealing Hidden Dynamics in AlphaFold3 Structure Predictions. SynBio, 3(4), 18. https://doi.org/10.3390/synbio3040018

Document Type

Peer-Reviewed Article

Publication Date

2025-11-14

Publisher

MDPI

Language

English

College

Computational, Mathematical and Physical Sciences

Department

Physics and Astronomy

University Standing at Time of Publication

Associate Professor

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