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 the intrinsic phi,psi propensities of amino acids free from the regular interactions associated with beta-strands and alpha-helices. We have considered the role of context on phi,psi preferences by examining the effects of neighbouring residues in modulating coil propensities within a data base of 512 high-resolution, low-homology structures. In the general case, when flanking residues are beta-branched or aromatic (Val, Ile, Tyr and Phe) the beta-propensity (Pbeta) increases significantly, largely due to steric effects between flanking residues. More subtle residue-specific effects are apparant when Pbeta values are examined in detail, showing "random coil" conformations to be highly sequence-dependent. The effects of flanking residues on phi distributions have been used to calculate context-dependent average 3JNH-Halpha 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-strand fragments of both hairpins. We find a better correlation between 3JNH-Halpha values derived from the data base model and those determined experimentally when context-dependent phi distributions are considered. The individual C-terminal beta-strand sequences (GKKITVSI versus GKKITKSK) of the two hairpins are predisposed to different extents to formation of an extended beta-like conformation. Conformational "predisposition" in this context may contribute significantly to beta-hairpin stability.