The Dominant Role of Side Chains in Beta-Sheets Aggregates

The rationalization of chemical and biological molecular recognition phenomena frequently relies on our understanding of weak noncovalent interactions, their magnitude, and their cooperative interplay. Quantitative analysis of individual binding contributions is problematic because individual interactions are seldom viewed in isolation but frequently as an incremental component of a stronger interaction. Synergistic effects that link one interactions with other neighboring interactions further complicate the analysis. Refolding of mainly ?-helical proteins into largely ?-sheet structures has been widely implicated in protein folding-related diseases states, including Alzheimer and BSE suggesting that model peptide ?-sheets may provide some insight into the underlying molecular basis for ?-sheet stabilization, self-association, and prion-like structural transformations. This work describes the use of chemical model systems to study the interactions and structural changes of ?-sheet aggregates interacting with bioactive sequences having twisted ?-strand. Chemical model systems provide an excellent vehicle with which to explore ?-sheets, because they are smaller, simpler and easier to manipulate than proteins. Antiparallel dimeric ?-strand formed by D,L-alternating peptides and three stranded ?-sheet peptide motifs derived from native protein sequences (or through rational design) may be suitable as vehicle for quantitative analysis of weak monovalenti interactions. Here we report about intermolecular interactions and conformational changes between dimeric ?-sheet and bioactive peptide that form preferentially a twisted dimeric conformation in solution.