Nucleation and the Transition State of the SH3 Domain

Citation:

Hubner, I.A., Edmonds, K.A. & Shakhnovich, E.I. Nucleation and the Transition State of the SH3 Domain. Journal of Molecular Biology 349, 2, 424 - 434 (2005).

Date Published:

2005

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 ϕ-values as structural constraints 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 ("probability to fold”, or pfold) 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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