Development and Application of Generalized Ensemble Algorithms for Protein Studies

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Professor Ulrich Hansmann is supported by the Theoretical Chemistry and Molecular Biophysics Programs to develop, distribute and apply generalized ensemble algorithms to the study of proteins. A primary emphasis of this work is on complicated methodological developments and subsequent export of resulting methodologies to other groups interested in large-scale simulation of biological processes. Specifically, Hansmann develops new means for computationally enhancing the frequency of transitions between interesting low-energy states. In addition, observed transitions are analyzed to determine chemically relevant reaction coordinates. Motivation is based on the need to increase simulation efficiency by an order of magnitude. This will be accomplished by inclusion of advanced physical concepts. In addition, an accurate means for accounting for solvent-solute interactions is being developed. Applications concentrate on investigating relative stabilities of and transitions between the helical and sheet-like structures of the b-amyloid peptide. Formation and aggregation of the sheet-like structures is a feature that is common to a number of neurological diseases.Proteins are a common yet important class of molecules in living systems. As enzymes, proteins catalyze and regulate a cell's biochemical reactions. As antibodies they contribute to the immune system. Since such functions are closely related to their three-dimensional shapes, small defects can cause misfolding which can cause a variety of diseases. Understanding these effects from computer simulation requires additional levels of complexity in both the theoretical models and in the computational approach employed to investigate the manifestations of the models. In addition to addressing the theoretical and computational issues for biochemical simulation, this work concentrates on understanding how misfolded structures of the b-amyloid peptide form and aggregate. The occurrence of such abnormal structures has been associated with Alzheimer's disease.