Synthesis and Comformational Study of Helix/Sheet Mimics

Miami University Oxford, Oxford OH

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Abstract

DESCRIPTION: (Applicant's Description) The long term objective of this project is related to the design arid synthesis of compounds with predictable structure and is related to the influence of hydrogen bonding on bets-sheet stability. The design of peptides and proteins with well-defined folding patterns continues to be a topic of widespread interest, bets-Sheets provide the key element in protein-DNA, protein-RNA, and protein-protein recognition. Aggregated protein fibrils exhibiting predominantly bets-sheet structure have been implicated in amyloid diseases (such as Alzheimer's disease). Although the studies of alpha-helical structures are extensive, the study of beta-sheet is still an area of under-explored. This project includes plans for the synthesis of several helix/sheet mimics made of 3(1) beta-peptides and strands of natural peptides. The conformational study of these hybrid peptides will be carried out by two-dimentional 1H NMR spectroscopy. The influence of inter-strand hydrogen bonding on B-sheet stability will be studied by deletion of hydrogen bonds. Several 3(1) helical bets-peptides will be prepared and each attached with two or three strands of natural peptides on its sidechains at the ith and i + 3 positions. These helical beta-peptides serve as a nucleators for the attached natural peptide strands to form beta-sheet like structures. The direction of the attached peptides can be controlled which leads to the formation of either a parallel or an antiparallel beta-sheet like structure. The solubility of the hybrid peptides can be controlled by using either hydrophilic or hydrophobic beta-amino acid residues for studies in either water or organic solvents, respectively. The helix/sheet models will be studied by two-dimensional 1H NMR spectroscopy. Each peptide will be studied by NOE difference spectroscopy, such as 2D-NOESY, to determine the degree of side-chain interactions. The contribution of hydrogen bonding to the stability of the B-sheets will be examined by replacing one strand of natural peptide with a strand of depsipeptide. Depsipeptides are known to have similar conformational preference as normal peptides but are deprived of hydrogen bonding capacity. Determination of the stability of the helix/sheet mimics before and after such a substitution should provide information on the importance of interstrand hydrogen bonding.