This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The assembly of normally soluble proteins into ordered aggregates, known as amyloid fibrils, is a cause or associated symptom of twenty-four different human disorders, including Alzheimers, Parkinsons and Huntingtons diseases, the prion diseases, and adult-onset diabetes. The molecular level mechanisms by which these proteins aggregate are still unclear. In an effort to shed light on this important phenomenon, we are investigating the aggregation of model fibril-forming peptides using molecular-level computer simulation. We have developed a protein model that accounts for the most important types of intra- and inter-molecular interactions - hydrogen bonding and hydrophobic interactions - while allowing the folding process to be simulated in a reasonable time frame. The model utilizes discontinuous potentials such as hard spheres and square wells in order to take advantage of discontinuous molecular dynamics (DMD), a fast simulation technique that is very computationally efficient. DMD will be used to examine the folding and aggregation of systems of model peptides ranging in size from eight to forty-eight peptides. The effects of chain length, concentration, temperature, interaction strengths, and system size will be studied.
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