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Title: Binding mechanisms and dynamic properities of sphingolipid binding peptides on lipid rafts : molecular dynamics simulation studies
Authors: Wang, Yaofeng
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2015
Source: Wang, Y. (2015). Binding mechanisms and dynamic properities of sphingolipid binding peptides on lipid rafts : molecular dynamics simulation studies. Doctoral thesis, Nanyang Technological University, Singapore.
Abstract: Since detergent-resistant membrane (ORM) domain was discovered in 1973, the structure of plasma membrane was not simply considered as the homogeneous fluid mosaic model any more. Separations between liquid-ordered (La) phase and disordered (Lef) phase in plasma membrane were identified. ORM domain, where the La phase is located, was identified to be enriched with sphingolipids and cholesterols, and so referred to as sphingolipid rafts or lipid rafts. Lipid rafts are involved in many secretary pathways. Several lines of evidence suggested that many hostpathogen/ toxin interactions were specifically located on lipid rafts, such as Alzheimer's disease, the lipid storage diseases as well as type II diabetes. Due to the nano-meter size of lipid raft domain, it is challenging to observe it directly. Therefore, a proper probe is needed to label the rafts domain. Sphingolipid binding peptides are good candidates to be the probe as the enrichment of sphingolipids in lipid rafts. Recently, several sphingolipid binding domain (SBD) were reported and fluorescently tagged SBO probe derived from A~1-25 was constructed and tested. This SBO probe has good binding affinity to variant ganglioside types in variant pH environments. However, structural details ofthe binding behaviors between A~ derived SBO and gangliosides have been poorly understood so far. For a better understanding about the binding process of SBO to lipid raft, molecular dynamics (MO) simulations were performed in this dissertation to investigate structural and dynamic details in the binding process. The mechanisms of SBD diffusion and condensation on lipid rafts were studied as well. In this study, first, native conformations of fluorescent SBO probe derived from A~l25 were explored by replica exchange molecular dynamics simulations. Furthermore, binding process between fluorescent A~1-25 SBO monomer and GTlb gangliosides raft-like lipid bilayer in neutral pH was obtained by extensive MD simulations. Both hydrophobic and electrostatic forces were identified to play critical roles in the binding process. The binding patterns of A~1-25 to the lipid raft were identified as helical conformation in wild type while helix-tum-helix in Kl6E mutant. The fluorescent dye and linker molecules in the probe were proved to be able to enhance the SBD folding and binding to the lipid raft. Furthermore, the binding behaviors between A~1-25 tetramer and GMI contained raft-like lipid bilayer in acid pH environment were studied. Helical conformations of SBD were protected at acid pH by binding to GMI lipids. In addition, the diffusion and condensation behaviors of SBD peptides on lipid rafts were produced by coarse grained molecular dynamics simulations. It was found that SBD bind to ganglioside head groups, and diffused with ganglioside lipids into La phase. And this' is probably the mechanism of SBD condensation on lipid raft. In summary our simulation data provided a vivid picture of the binding process of SBD peptide interacting with lipid rafts. We hope such study may provide a theoretical foundation for optimum design of lipid rafts probes.
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