CAREER: Computational studies of the structure and biological activity of amyloid forming peptides

点击翻译按钮获取中文摘要

0952624ZhengAmyloid peptides have a strong membrane associated ability that can induce cytotoxicity to neurons by altering membrane integrity and permeability. Accumulating evidences suggest that (i) soluble, low molecular weight amyloid oligomers are major toxic species and (ii) the cytotoxicity leading to the cell death could be mediated by direct interactions between amyloid oligomers and cell membrane. However, the molecular mechanism underlying peptide-mediated lysis, i.e. whether these peptides form pores or induce membrane defects, remains unclear at the atomic level. The lack of detailed oligomer structures and the involvement of complex natural cell membrane have hampered efforts to establish a direct correlation between oligomer structural transition from the aqueous to the membrane environment and their biological activity in cell membranes. Intellectual Merit: The most important goal of this project is to establish the generality of the mechanism of toxicity caused by amyloid peptides, with particular attention to two types of amyloid peptides (Aâ from Alzheimer disease vs. K3 of â2-microglobulin from hemodialysis) and two membrane interaction models (reside on the membrane vs. embed in the membrane), using a four step computational strategy coupled with different computational approaches. The specific aims of this proposal are: (i) to predict amyloid oligomers using an in house peptide packing program, (ii) to identify stable amyloid oligomers in solution, (iii) to determine toxic membrane bound oligomers and their related mechanism of membrane disruption, and (iv) to design mutants and ligands to disrupt the formation of stable toxic oligomers. The proposed synergistic four step computational strategy can be also applied to study other protein misfolding diseases such as Parkinson's and Prion diseases. Funding of this proposal will allow PI's group to extend current simulation works to capture amyloid oligomers using well controlled self-assembled monolayers and to develop polymer based inhibitors to prevent oligomer formation in experiments. In a broader context, knowing the detailed structures of amyloid oligomers and understanding their molecular behavior with lipids will (i) advance our fundamental understanding of amyloid toxicity mechanism and (ii) rationally design drugs for inhibiting amyloid formation. Broad Impact: The PI is collaborating with various experimental and theoretical groups in academia and national laboratories on this anti amyloid project. Through this research, a molecular level understanding of the relationship between structure, stability, and biological activity of misfolded protein aggregates and cell membranes can be obtained, which is vital in the development of therapeutic strategies against neurodegenerative diseases such as Alzheimer's, Parkinson's, and diabetes II, benefiting both scientific community and entire society. The project will also educate graduate, undergraduate, and precollege students, particularly those from underrepresented groups, to the concepts and simulation tools for studying protein aggregates. The discoveries and methods from this proposal will be incorporated into a new course of Molecular Modeling and Simulation of Biomolecular Systems and an existing undergraduate thermodynamics course. The knowledge derived from the proposal will be disseminated through publications, presentations, workshops, courses, internships, and other outreach activities.