Misfolded proteins become aberrantly enriched in beta-sheet secondary structure, regardless of their amino-acid sequence. The chemical features of proteins that create this intrinsic bias remain unclear. Our lab is performing precision molecular dissection to identify the chemical interactions that bias proteins toward misfolding.
Beta-strands are the basic structural units of protein beta-sheets, which in turn are both a fundamental component of native protein structures and a frequent feature of toxic misfolded proteins. Understanding the fundamental chemical determinants that drive beta-strand formation is therefore important for protein modeling, design, and drug discovery; however, isolated strands have little conformational stability, and the chemical forces that bias the polypeptide toward this structure remain unclear. Moreover, it has been difficult to dissect the role of individual beta-strands in protein folding and stability due to a lack of probes that selectively perturb and/or report strand formation. We discovered that hydrogen bonds can form within individual beta-strands, potentially organizing protein folding and misfolding. We are currently performing molecular dissections of model proteins to determine how local conformational preferences stabilize protein folds, accelerate protein folding, and shape beta-sheet topology.