AbstractsBiology & Animal Science

Biological membranes function as an essential barrier between living cells and their environments. The membrane associated peptides (MAPs) interact with membrane either to facilitate the energy and molecules exchange between the environments and cytoplasm (e.g. cell-penetrating peptide), or to disturb the membrane and cause deadly membrane leakage (e.g. amyloid peptides and antimicrobial peptides). The structures and activity of these peptides are essential to understand the membrane association mechanisms and to screen the drug candidates. However, the poor atomic details of MAPs membrane-bound structures and their complicated interactions with cell membranes leads to the difficulty to better understand their biological roles. As the structures of MAPs are the prerequisite, in this dissertation, the structure prediction and screening of MAPs were firstly performed in Chapter II, Chapter III, and Chapter IV. We selected amyloid peptides as they usually form complicated polymorphic oligomeric structures, which are the most toxic species. Misfolding and self-assembly of human islet amyloid polypeptide (hIAPP, one of amyloid peptides which belong to MAPs) monomer into polymorphic amyloid oligomers is pathologically linked to type II diabetes. We developed a structures-screening program base on GBMV implicit-solvent evaluation and a structure population evaluation program by Monte Carlo simulation to search the aggregated structures of hIAPP with dominant populations. After the structure search, the stacking-sandwich model and wrapping-cord model were proposed to describe polymorphic structures of hIAPP oligomers, and all-atom molecular dynamics simulations were used to examine the structure, dynamics, and association of the self-assembled hIAPP oligomers. Seven oligomers from the stacking-sandwich model and three oligomers from the wrapping-cord model were determined by their high structural stability with favorable peptide-peptide interactions, although all of them displayed completely different structures in symmetry and beta-sheet packing. These oligomeric structures can also serve as templates to present double- and triple-stranded helical fibrils via peptide elongation, explaining the polymorphism of amyloid oligomers and fibrils. Base on the predicted oligomeric structures, the mechanisms of amyloid toxicity can be studied. The leaking pore mechanism is more and more widely accepted, in which the amyloid peptides form an ion channel-like but unregulated pore structures. We further investigated the dynamic structures, ion conductivity, and membrane interactions of hIAPP pores in the DOPC bilayer using molecular dynamics simulations (Chapter V and Chapter VI). In the simulated lipid environments, a series of annular-like hIAPP structures with different sizes and topologies were compatible with the doughnut-like images obtained by atomic force microscopy (AFM) and with those of modeled channels for Abeta, K3 peptide, and antimicrobial peptide PG-1, suggesting that loosely-associated beta-structure motifs can be a…