Modulation of intrinsic phi,psi propensities of amino acids by neighbouring residues in the coil regions of protein structures: NMR analysis and dissection of a beta-hairpin peptide

Analysis of residues in coil regions of protein structures presents a novel approach to deconvoluting the various competing factors which determine th e intrinsic phi, psi propensities of amino acids free from the regular inte ractions associated with beta-strands and alpha-helices. We have considered the role of context on phi, psi preferences by examining the effects of ne ighbouring residues in modulating coil propensities within a data base of 5 12 high-resolution, low-homology structures. In the general case, when flan king residues are beta-branched or aromatic (Val, Ile, Tyr and Phe) the bet a-propensity (P-beta) increases significantly, largely due to steric effect s between flanking residues. More subtle residue-specific effects are appar ant when P-beta values ape examined in detail, showing "random coil" confor mations to be highly sequence-dependent. The effects of flanking residues o n phi distributions have been used to calculate context-dependent average ( 3)J(NH-H alpha) coupling constants. We have examined these findings in the context of the folding of a model 16-residue beta-hairpin peptide, "mutant" hairpin (VSI --> KSK sequence change) and the isolated C-terminal beta-str and fragments of both hairpins. We find a better correlation between (3)J(N H-H alpha) values derived from the data base model and those determined exp erimentally when context-dependent phi distributions are considered. The in dividual C-terminal beta-strand sequences (GKKIT<(VSI)under bar> versus GKK IT<(KSK)under bar>) of the two hairpins are predisposed to different extent s to formation of an extended beta-like conformation. Conformational "predi sposition" in this context may contribute significantly to beta-hairpin sta bility. (C) 1998 Academic Press.