Navigating protein landscapes with a machine-learned transferable coarse-grained model
Journal article, 2025
The most popular and universally predictive protein simulation models employ all-atom molecular dynamics, but they come at extreme computational cost. The development of a universal, computationally efficient coarse-grained (CG) model with similar prediction performance has been a long-standing challenge. By combining recent deep-learning methods with a large and diverse training set of all-atom protein simulations, we here develop a bottom-up CG force field with chemical transferability, which can be used for extrapolative molecular dynamics on new sequences not used during model parameterization. We demonstrate that the model successfully predicts metastable states of folded, unfolded and intermediate structures, the fluctuations of intrinsically disordered proteins and relative folding free energies of protein mutants, while being several orders of magnitude faster than an all-atom model. This showcases the feasibility of a universal and computationally efficient machine-learned CG model for proteins.
Author
Nicholas E. Charron
Rice University
Freie Universität Berlin
Zuse Institute Berlin (ZIB)
Klara Bonneau
Freie Universität Berlin
Aldo S. Pasos-Trejo
Freie Universität Berlin
Andrea Guljas
Freie Universität Berlin
Yaoyi Chen
Freie Universität Berlin
Felix Musil
Freie Universität Berlin
Jacopo Venturin
Freie Universität Berlin
Daria Gusew
Freie Universität Berlin
Iryna Zaporozhets
Rice University
Freie Universität Berlin
Andreas Kraemer
Freie Universität Berlin
Clark Templeton
Freie Universität Berlin
Atharva Kelkar
Freie Universität Berlin
Aleksander E. P. Durumeric
Freie Universität Berlin
Simon Olsson
Chalmers, Computer Science and Engineering (Chalmers), Data Science and AI
University of Gothenburg
Adria Perez
University Pompeu Fabra
Acellera
Maciej Majewski
University Pompeu Fabra
Acellera
Brooke E. Husic
Princeton University
Ankit Patel
Baylor College of Medicine
Rice University
Gianni De Fabritiis
Catalan Institution for Research and Advanced Studies
University Pompeu Fabra
Acellera
Frank Noe
Rice University
Freie Universität Berlin
Microsoft Research
Cecilia Clementi
Rice University
Freie Universität Berlin
Nature Chemistry
1755-4330 (ISSN) 1755-4349 (eISSN)
Vol. 17 8 1284-1292Subject Categories (SSIF 2025)
Theoretical Chemistry
Bioinformatics (Computational Biology)
Biophysics
DOI
10.1038/s41557-025-01874-0
PubMed
40681718