  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.
