Molecular dynamics simulations of oligopeptides in solution will be used to study the ways in which hydrogen bonds characteristic of protein secondary structure are made and broken. Structures considered will include 13-membered rings closed by a hydrogen bond (found in alpha-helices) and 10-membered rings (found in beta-turns and 3-10 helices). The simulations will consider both sequences known (by NMR analysis) to contain significant populations of secondary structure as well as sequences of more general interest (e.g. X-Pro-Gly-X for the case of tight turns.) Two general computational approaches will be used: in the first, "umbrella" sampling techniques will generate free energy profiles (potentials of mean force) for reaction coordinates corresponding to making or breaking particular hydrogen bonds. The second approach will use thermodynamic perturbation theory to estimate the free energy changes due to sequence changes for both folded and "random" conformers. The polypeptides studied will be from four to twelve amino acids in length. This work should have important application in understanding the earliest events in protein folding, when initial pieces of secondary structure are formed. In addition, a deeper understanding of the solution structure of polypeptides should aid in the design of novel peptide hormones and neurotransmitters. Antibodies to peptides appear to recognize nascent structures similar to those seen in a corresponding sequence in intact proteins; hence, an understanding of the forces and sequence specificity involved in forming internal hydrogen bonds in polypeptides may aid in understanding antibody-antigen recognition and in the design of synthetic vaccines. The study will be carried out in parallel with NMR analyses of polypeptides from the laboratory of Dr. Peter Wright. Sequences studied by both experimental and theoretical techniques will include those derived from influenza virus hemagglutinin, from a malaria parasite circumsporozite protein, and from myohemerythrin.