Folding of a highly conserved diverging turn motif from the SH3 domain.

ABSTRACT: Recent NMR structural characterization studies showed that a seven-residue segment (FKKGERL) from the src SH3 domain adopts the nativelike diverging type II beta-turn in aqueous solution in support of the prediction based on the I-sites library of sequence structural motifs. We study the conformational variability and folding/unfolding thermodynamics of this peptide in explicit solvent using replica-exchange molecular dynamics simulations, which greatly enhances the sampling of the conformational space. This peptide samples three main free energy basins (nativelike, intermediate, and unfolded) separated by small barriers. The nativelike basin is fractionally populated (DeltaG(300K) = 0.4 kcal/mol) with structures that satisfy a subset of the NMR-derived constraints. The intrinsic stability of the diverging turn is examined in relationship to the nature of three specific contacts: a turn-hydrogen bond, a mainchain-to-sidechain hydrogen bond, and an end-to-end hydrophobic contact. We have carried out simulations of mutants at the highly conserved GE positions in the sequence. The mutation E5D destabilizes the isolated diverging turn motif, contrary to the observation that this mutation stabilizes the fyn SH3 domain. The G4T mutation also destabilizes the isolated diverging turn; however, the extent of destabilization is smaller than that of the reverse mutation in the drk SH3.

SUBMITTER: Gnanakaran S 

PROVIDER: S-EPMC1302727 | biostudies-literature | 2003 Mar

REPOSITORIES: biostudies-literature