Native contacts determine protein folding mechanisms in atomistic simulations

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 44; pp. 17874 - 17879
• Main Authors: Best, Robert B., Hummer, Gerhard, Eaton, William A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.10.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Amino acids; Bayes Theorem; Bayesian analysis; Biological Sciences; Coordinate systems; Free energy; Kinetics; Modeling; Models, Chemical; Molecular dynamics; Molecular Dynamics Simulation; Physical Sciences; Protein Folding; Simulation; Simulations; Trajectories; Ubiquitins; Gō models; reaction coordinate; funnel; internal friction; frustration
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1311599110

The recent availability of long equilibrium simulations of protein folding in atomistic detail for more than 10 proteins allows us to identify the key interactions driving folding. We find that the collective fraction of native amino acid contacts, Q , captures remarkably well the transition states for all the proteins with a folding free energy barrier. Going beyond this global picture, we devise two different measures to quantify the importance of individual interresidue contacts in the folding mechanism: (i) the log-ratio of lifetimes of contacts during folding transition paths and in the unfolded state and (ii) a Bayesian measure of how predictive the formation of each contact is for being on a transition path. Both of these measures indicate that native, or near-native, contacts are important for determining mechanism, as might be expected. More remarkably, however, we found that for almost all the proteins, with the designed protein α ₃D being a notable exception, nonnative contacts play no significant part in determining folding mechanisms.