Prediction of structural stability of short beta-hairpin peptides by molecular dynamics and knowledge-based potentials

We tested the new approach on four families of short β-hairpin peptides: TrpZip, MBH, bhpW and EPO, whose structural stabilities have been experimentally measured in previous studies. For all four families, both computational techniques show considerable correlation (r > 0.65) with the experimentally measured stabilities. The consensus of the two techniques shows higher correlation (r > 0.82).Our results suggest a prediction scheme that can be used to estimate the relative structural stability within a peptide family. We discuss the applicability of this predictive approach for in-silico screening of combinatorial peptide libraries.Peptides are important constituents of biological systems. They often initiate signal transduction cascades by binding and activating membrane-bound receptors [1,2]. Many therapeutic peptides exert their activity by binding to these receptors, and either activating [3] or blocking them [4]. Another type of peptide therapeutic activity is the prevention of disease-related protein-protein interactions. In this case, peptides derived from one of the proteins compete against it over the interaction site [5].In all these cases the key to the therapeutic effect is high affinity binding of the peptide to a specific site in the target protein. This, in turn, depends on the peptide's ability to adopt a binding-site-compatible conformation. The more stable this conformation is, the higher the affinity [6,7] due to the lower entropic price of binding. Structural stability of the bound conformation also affects the specificity of binding, because of the inverse correlation between stability and the accessibility to alternative binding conformations. Natural peptides are often rather flexible and long and may achieve specificity and affinity by binding to side-sites. Therapeutic peptide and peptide-like agents, on the other hand, must be kept short for pharmaceutical reasons, and their development often involves rigidification [6-8].The search for spe