Exploring β-Sheet Structure and Interactions with Chemical Model Systems

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Abstract
This Account describes my research group’s use of chemical model systems to study the structure and interactions of β-sheets. Chemical model systems provide an excellent vehicle with which to explore β-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 β-sheets”, molecular template and turn units are combined with peptides to mimic the structures of parallel and antiparallel β-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 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. Artificial β-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 β-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 β-sheets. These studies help illustrate the importance of intermolecular edge-to-edge interactions between β-sheets in peptides and proteins. Ultimately, these model systems may lead to new ways of controlling β-sheet interactions and treating diseases in which they are involved.