This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.We propose to work on two projects, both are related to self-aggregation and self-assembly of peptides or proteins and both are stimulated by recent experiments by our collaborators. Peptide or protein aggregation is a problem of much current interest, because of its close relation to neurodegenerative diseases, such as Alzheimers disease, and its relation to biomaterials, such as hydrogels. Although many researchers are working on different aspects of the problems, due to their complexity, many questions remain. In the first project, we shall study the structures and dynamic behaviors of peptides, (AAKA)_n, n= 3, 4. Since Schweitzer-Stenner and coworker have shown that, in proper solution conditions, these peptides self-aggregate into hydrogels and the processes take place via a PPII -> beta-sheet or alpha-helix -> beta-sheet transitions. To provide structure information of the systems and to investigate how transitions into beta-sheet structure take place, we shall study these systems using implicit-solvent molecular dynamics (MD) simulations. The goals are to find the low-energy conformations, their populations, and possible transitions between them. One important way to achieve these goals is to calculate the free energy landscape of the systems in terms of two reaction coordinates, such as the radius of gyration and the end-to-end distance, or the fraction of native contacts. To reduce trapping into local free energy minima, multi-histogram and replica exchange methods will be used for the MD simulations. In the second projects, recent single-pair fluorescence energy transfer (spFRET) experiments by Hai-Lung Dais group will be simulated, in which they have observed donor-to-acceptor energy transfers between beta-amyloid dimers (Abeta 1-40). These dimers are made of monomers tagged by donors or acceptors at the N-terminus, respectively. When dimers are formed by donor-tagged and acceptor-tagged monomers, spFRET can be observed. To confirm and interpret their experimental results, it is important to know the conformations of monomer, dimer, or oligomers. MD methods similar to those discussed above will be used to study the conformations, their populations, and free energy landscapes of a single Abeta molecule as well as an Abeta dimer.
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