With the support of the Organic Dynamics Program in the Chemistry Division, Professors Igor Lednev and John Welch of the Chemistry Department at the State University of New York at Albany (SUNY-Albany) will perform research where the long-term goal is to identify the crucial intermolecular interactions involved in the folding and fibrillation of proteins. Beta-Sheet folding in large synthetic, fibrillogenic polypeptides will be investigated by establishing the primary sequence-property relationship governing beta-sheet nucleation and the role of aggregation on formation of beta-sheet nucleus. The mechanism of folding will be determined using deep UV resonance Raman (DUVRR) spectroscopy combined with advanced statistical analysis including 2D-correlation spectroscopy. The variation of polypeptide length and selective site-specific introduction of beta-hairpins will enable determination of the role of intra- and intermolecular folding initiation. The selective control of amino acid sequence possible by using genetically engineered polypeptides as models for native protein folding will enable careful investigation of the influence of polypeptide charge and electrolyte interactions on folding, both properties associated with the in vivo folding of amyloidogenic proteins. With a firm understanding of the influence of primary sequence on folding, the effect of templating will be investigated. The researchers hope to understand what changes in an aggregate structure compromises its ability as a template.
This research by Professors Lednev and Welch of SUNY-Albany will address the fundamental biophysics behind folding processes and may lead to insights, made possible by the use of simplified model compounds that may also have relevance to the basis for disease states with protein misfolding etiology. The research results clearly have direct applicability to understanding the etiology of protein deposition diseases, such as the neurodegenerative diseases Alzheimer's, Parkinson's, and Creutzfeld-Jacob diseases. This cross-disciplinary project will train undergraduate and graduate students in biophysics, biochemistry and molecular biology thus preparing future professional scientists and engineers with multidisciplinary backgrounds and versatile skills. Professors Lednev and Welch will continue to involve undergraduate students from historically underrepresented groups in their research projects. The advanced knowledge acquired through this NSF funded program will be integrated into undergraduate and graduate courses.
