Exploring β-Sheet Structure and Interactions with Chemical Model Systems

Abstract

Beta-sheets consist of extended polypeptide strands (beta-strands) connected by a network of hydrogen bonds and occur widely in proteins. Although the importance of beta-sheets in the folded structures of proteins has long been recognized, there is a growing recognition of the importance of intermolecular interactions among beta-sheets. Intermolecular interactions between the hydrogen-bonding edges of beta-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. The importance of beta-sheet interactions in biological processes makes them potential targets for intervention in diseases such as AIDS, cancer, and Alzheimer's disease. This Account describes my research group's use of chemical model systems to study the structure and interactions of beta-sheets. Chemical model systems provide an excellent vehicle with which to explore beta-sheets, because they are smaller, simpler, and easier to manipulate than proteins. 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. In our "artificial beta-sheets", molecular template and turn units are combined with peptides to mimic the structures of parallel and antiparallel beta-sheets. The templates and turn units form folded, hydrogen-bonded structures with the peptide groups and help prevent the formation of complex, ill-defined aggregates. Templates that duplicate the hydrogen-bonding pattern of one edge of a peptide beta-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. Artificial beta-sheets that present exposed hydrogen-bonding edges can form well-defined hydrogen-bonded dimers. Dimerization occurs readily in chloroform solutions but requires additional hydrophobic interactions to occur in aqueous solution. Interactions among the side chains, as well as hydrogen bonding among the main chains, are important in dimer formation. NMR studies of artificial beta-sheets have elucidated the importance of hydrogen-bonding complementarity, size complementarity, and chiral complementarity in these interactions. These pairing preferences demonstrate sequence selectivity in the molecular recognition between beta-sheets. These studies help illustrate the importance of intermolecular edge-to-edge interactions between beta-sheets in peptides and proteins. Ultimately, these model systems may lead to new ways of controlling beta-sheet interactions and treating diseases in which they are involved.