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Nucleation and the transition state of the SH3 domain

Isaac A. Hubner·Katherine A. Edmonds·Eugene I. Shakhnovich
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Abstract

We present a verified computational model of the SH3 domain transition state (TS) ensemble. This model was built for three separate SH3 domains using experimental s in all-atom protein folding simulations. While averaging over all conformations incorrectly considers non-TS conformations as transition states, quantifying structures as pre-TS, TS, and post-TS by measurement of their transmission coefficient (pfold, or probability to fold) allows for rigorous conclusions regarding the structure of the folding nucleus and a full mechanistic analysis of the folding process. Through analysis of the TS, we observe a highly polarized nucleus in which many residues are solvent-exposed. Mechanistic analysis suggests the hydrophobic core forms largely after an early nucleation step. SH3 presents an ideal system for studying the nucleation-condensation mechanism and highlights the synergistic relationship between experiment and simulation in the study of protein folding.

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Isaac A. Hubner, Katherine A. Edmonds, Eugene I. Shakhnovich. 2005-03-17. Nucleation and the transition state of the SH3 domain. https://arxiv.org/abs/q-bio/0503027

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