MOLECULAR-DYNAMICS SIMULATIONS OF PEPTIDE-FRAGMENTS FROM HEN LYSOZYME- INSIGHT INTO NONNATIVE PROTEIN CONFORMATIONS

Molecular dynamics simulations of four peptides taken from the hen lys ozyme sequence have been used to generate models for non-native protei n conformations. Comparisons between the different peptides and with e xperimental data for denatured lysozyme and peptide fragments provides insight into the characteristics of the conformational ensembles popu lated in these non-native states and the dependence of their structura l features on the amino acid sequence. For the denatured conformers po pulated local contacts dominate in determining the properties observed in the trajectories, all four peptides showing similar characteristic s. These include a significant increase in the number of main-chain O( i)-NH(i + 2) hydrogen bonds and hydrogen bonds involving side-chain gr oups, this increase compensating to a large extent for the loss of hyd rogen bonds involved in helical or beta-sheet secondary structure in t he native fold, and the generation of a population of collapsed states with local clusterings of hydrophobic groups. The hydrophobic cluster s enable at least partial burial of many side-chains exposed by the lo ss of tertiary contacts on denaturation and provide models that may ex plain the experimentally observed protection of amides from hydrogen e xchange and the existence of residual secondary structure in non-nativ e species of lysozyme. The results suggest that this approach has an i mportant role to play in aiding the interpretation of experimental dat a for conformationally disordered non-native states of proteins. (C) 1 998 Academic Press.