Multi-scale Molecular Dynamics Simulations of Membrane-associated Peptides PDF Download

Author: Jun Zhao
Publisher:
ISBN:
Category : Amyloid
Languages : en
Pages : 280

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Book Description
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 molecules exchange between the environments and cytoplasm (e.g. cell-penetrating peptide), or to disturb the membrane (e.g. amyloid peptides and antimicrobial peptides). The structures and activity of these peptides are essential to understand the mechanisms and to screen the drug candidates. Thus, in this dissertation, the structure prediction and screening of MAPs were firstly performed in Chapter II, III, and IV. 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 amyloid peptide hIAPP with dominant populations. Seven stacking-sandwich models and three the wrapping-cord models were determined, which 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. 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 VI). Our results suggested that loosely-associated [Beta]-structure motifs can be a general feature of toxic, unregulated channels. The process how MAPs adsorb on membrane and further penetrate across the membrane was futher evaluated by the transmembrane potential mean force (PMF). We constructed an effect platform including adaptive biasing force (ABF) method which accelerates the membrane penetration process, umbrella sampling method which effectively generates trans-membrane PMFs, and MARTINI coarse-grained force field to measure the free energy required to transfer the MAPs from bulk water phase to water-membrane interface, and further to bilayer interior (Chapter VII). The results implied that biological activity of antimicrobial peptides appeared to be closely related to their trans-membrane ability indicated by the PMF profiles. Moreover, due to the complicated components of cell membrane, it is better to simplify the interactions between MAP-membrane to MAP-artificial surfaces. Thus, in the last part of the dissertation, we further presented a series of exploratory molecular dynamics (MD) simulations to study the early adsorption and conformational change of amyloid peptide [Amyloid-beta] oligomers from dimer to hexamer on three different self-assembled monolayers (SAMs) (Chapter VIII). Within the timescale of MD simulations, the conformation, orientation, and adsorption of [Amyloid-beta] oligomers on the SAMs was determined by complex interplay among the size of [Amyloid-beta] oligomers, the surface chemistry of the SAMs, and the structure and dynamics of interfacial waters.