title: Nucleation and the transition state of the SH3 domain.
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 phi-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 p(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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Isaac A
authors.initials: IA
authors.lastname: Hubner
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Edmonds
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013049:Spectrin / Q000737:chemistry*; D018909:src Homology Domains
chemical_list: D012997:Solvents; D013049:Spectrin; D011505:Protein-Tyrosine Kinases