Binding and Membrane Damage Behaviors of Self-Aggregated Beta-Amyloid Oligomers on Lipid Raft Surfaces from Microsecond Molecular Dynamics Simulations

Our hypothesis is that self-aggregated Beta-Amyloid Oligomers can bind to phase-separated lipid nanodomains and damage the membrane structures. The data were generated by microsecond molecular dynamics simulations of the binding events of beta-amyloid oligomers to phase-separated lipid rafts with or without glycolipid clusters, i.e., GM-raft or CO-raft. The lipid domain preference and binding energies of disordered amyloid aggregate to highly dynamic and heterogeneous lipid bilayers in structurally specific lipid nanodomains, e.g., glycolipid-clusters, cholesterol-enriched liquid-ordered (Lo) or cholesterol-depleted liquid-disordered (Ld), or mixed Lo/Ld (Lod) region, and annular lipid shells surrounding the membrane-bound protein, provide helpful insight into guiding future experiments to understand the regulation of lipid composition and structures on amyloid binding to cell membranes. The information is also helpful for the design of drug interventions and novel imaging markers targeting membrane-bound amyloidogenic oligomers. The results will guide the new design of single-molecule experiments aiming at understanding amyloidogenic proteins binding to complex but realistic lipid membranes, containing multiple lipid components and varying domain sizes and structures. The details of the procedures of modeling and simulations of beta-amyloid oligomers in lipid rafts have been described in a research article by Pham, T. and K.H. Cheng, Exploring the Binding Kinetics and Behaviors of Self-Aggregated Beta-Amyloid Oligomers to Phase-Separated Lipid Rafts with or without Ganglioside-Clusters. Biophysical Chemistry, 2022. (https://www.sciencedirect.com/science/article/abs/pii/S0301462222001168) This work has been supported by the Robert A. Welch Foundation [W-2057-20210327], National Science Foundation [OAC 153159], National Institutes of Health [RCC1GM090897], Williams Endowment for Interdisciplinary Physics and Murchison Undergraduate Research Fellowship of Trinity University.

本研究的核心假设为：自聚集β-淀粉样蛋白低聚物（self-aggregated Beta-Amyloid Oligomers）可结合至相分离脂质纳米域，并破坏细胞膜结构。本数据集通过微秒级分子动力学模拟生成，模拟对象为β-淀粉样蛋白低聚物与含/不含糖脂簇（glycolipid clusters）的相分离脂筏（lipid rafts）的结合事件，具体分为GM脂筏（GM-raft）与CO脂筏（CO-raft）两类。
针对结构特异性脂质纳米域（如糖脂簇、富含胆固醇的有序液态（liquid-ordered, Lo）域、贫胆固醇的无序液态（liquid-disordered, Ld）域，或混合Lo/Ld（Lod）域）中高度动态且具有异质性的脂质双层，无序淀粉样蛋白聚集体的脂质域偏好性、结合能，以及膜结合蛋白周围的环状脂质壳层，可为阐释脂质组成与结构对淀粉样蛋白结合细胞膜的调控机制提供关键见解，进而指导未来相关实验的开展。
该数据集信息亦可用于靶向膜结合淀粉样蛋白低聚物的药物干预方案设计与新型成像标记物开发。本研究结果将指导单分子实验的全新设计，旨在阐释淀粉样蛋白与含多种脂质组分、且域尺寸与结构各异的复杂且贴合生理真实情况的脂质膜的结合过程。
脂筏中β-淀粉样蛋白低聚物的建模与模拟流程细节已发表于Pham T与K.H. Cheng的研究论文：《Exploring the Binding Kinetics and Behaviors of Self-Aggregated Beta-Amyloid Oligomers to Phase-Separated Lipid Rafts with or without Ganglioside-Clusters》，刊载于《生物物理化学》（Biophysical Chemistry）2022年。（链接：https://www.sciencedirect.com/science/article/abs/pii/S0301462222001168）
本研究得到罗伯特·A·韦尔奇基金会（Robert A. Welch Foundation）[W-2057-20210327]、美国国家科学基金会（National Science Foundation）[OAC 153159]、美国国立卫生研究院（National Institutes of Health）[RCC1GM090897]、威廉姆斯跨学科物理捐赠基金以及三一大学默奇森本科生研究奖学金的支持。