The studies began with the development of chemical models of protein β-sheets in which molecular templates induce β-sheet structure in attached peptide strands in chloroform solution. Ultimately, these model systems may lead to new ways of controlling β-sheet interactions and treating diseases in which they are involved.ĭuring the past seventeen years, my co-workers and I have studied β-sheet structure and interactions by developing peptide-based chemical model systems in which synthetic building blocks of our own design help induce β-sheet folding, structure, and interactions. These studies help illustrate the importance of intermolecular edge-to-edge interactions between β-sheets in peptides and proteins. These pairing preferences demonstrate sequence selectivity in the molecular recognition between β-sheets. NMR studies of artificial β-sheets have elucidated the importance of hydrogen-bonding complementarity, size-complementarity, and chiral complementarity in these interactions. Interactions among the side chains, as well as hydrogen bonding among the main chains, are important in dimer formation. Dimerization occurs readily in chloroform solutions but requires additional hydrophobic interactions to occur in aqueous solution. Templates that duplicate the hydrogen-bonding pattern of one edge of a peptide β-strand while blocking the other edge have proven particularly valuable in preventing aggregate formation and in promoting the formation of simple monomeric and dimeric structures.Īrtificial β-sheets that present exposed hydrogen-bonding edges can form well-defined hydrogen-bonded dimers.

The templates and turn units form folded, hydrogen-bonded structures with the peptide groups and help prevent the formation of complex, ill-defined aggregates. In our “artificial β-sheets”, molecular template and turn units are combined with peptides to mimic the structures of parallel and antiparallel β-sheets. Synthetic chemical models also provide the opportunity to control or modulate natural systems or to develop other useful applications and may eventually lead to new drugs with which to treat diseases. Chemical model systems provide an excellent vehicle with which to explore β-sheets, because they are smaller, simpler, and easier to manipulate than proteins. This Account describes my research group’s use of chemical model systems to study the structure and interactions of β-sheets. The importance of β-sheet interactions in biological processes makes them potential targets for intervention in diseases such as AIDS, cancer, and Alzheimer’s. Intermolecular interactions between the hydrogen-bonding edges of β-sheets constitute a fundamental form of biomolecular recognition (like DNA base pairing) and are involved protein quaternary structure, protein-protein interactions, and peptide and protein aggregation. Although the importance of β-sheets in the folded structures of proteins has long been recognized, there is a growing recognition of the importance of intermolecular interactions among β-sheets. Β-Sheets consist of extended polypeptide strands (β-strands) connected by a network of hydrogen bonds and occur widely in proteins. “What I cannot create, I do not understand.

Beta sheet peptide backbone