Distributed REMD Simulation for Probing Alzheimer Molecular Mechanisms

项目摘要 ABeta多肽的聚集与阿尔茨海默病有关，阿尔茨海默病是最常见的痴呆症。ABeta细胞毒性的确切原因尚不清楚，但可能与ABeta多肽与细胞膜的相互作用有关，从而导致它们的破坏。目前，ABeta-膜相互作用的分子机制尚不清楚。使用显式处理的溶剂的全原子分子动力学模拟可以揭示这些机制，而这些机制是其他方法所不能获得的详细程度。然而，由于此类仿真的极端要求，现有的计算平台并不够用。为了解决这些局限性，我们提出了一种新的副本交换分子动力学(REMD)模拟器，以适应大规模并行网格计算体系结构--由Parabon Computation开发的Frontier企业计算平台。由于Frontier可以利用全球数万台计算机的空闲计算能力，并将其作为基于Web的服务提供，我们预计启用Frontier的版本REMD(称为dREMD)将允许研究人员从任何标准的Web浏览器以及时和负担得起的方式捕获REMD的全部潜力。 该项目的具体目标包括根据学术首席调查员开发的现有内部REMD代码开发dREMD软件。通过将dREMD模拟器的功能与在Linux集群上执行的常规REMD结果和实验数据进行比较，将对dREMD模拟器进行彻底测试。然后，我们将应用dREMD来探索ABETA-脂质双层相互作用的热力学。通过自由能计算，我们将研究ABeta单体和齐聚物结合和插入细胞双层的分子机制。我们的目标将是确定ABETA寡聚体干扰或破坏双层的能力。这些特定目标的实现将使Parabon公司为第二阶段STTR项目奠定基础，该项目将扩大dREMD的可用性特征，并将其应用于ABeta诱导的脂质双层中断的抑制剂的研究。业务目标是向市场推出两种产品：(1)Parabon Frontier Computation Grid顶部的dREMD，作为一种按使用付费的服务，向进行结构生物学和配体结合研究的制药和生物技术公司提供；(2)与Frontier Enterprise一起打包的dREMD，用于在内部提供相同的功能。 该项目的生物医学意义是双重的。首先，该项目有望通过向研究界提供一种新的强大的计算工具-dREMD来改变生物分子模拟的实践。DREMD具有通用性、价格低廉、使用方便等特点，它将把生物分子模拟的范围扩展到新的具有挑战性的问题。其次，该项目有望为阿尔茨海默病中涉及的ABeta肽细胞毒性机制提供新的线索。

Project Summary Aggregation of ABeta peptides is linked to Alzheimer's disease, the most common dementing disorder. The exact cause of ABeta cytotoxicity remains uncertain, but it may be related to the interactions of ABeta peptides with cellular membranes leading to their disruption. Currently, molecular mechanisms of ABeta-membrane interactions are largely unknown. All-atom molecular dynamics simulations with explicitly treated solvent can uncover these mechanisms with the level of detail not available through other methods. However, due to extreme demands of such simulations, existing computational platforms are not adequate. To address these limitations, we propose a novel adaptation of replica exchange molecular dynamics (REMD) simulator to a massively parallel grid computing architecture, the Frontier¿ Enterprise Computing Platform developed by Parabon Computation. Because Frontier can harness the idle computing power of tens of thousands of computers worldwide and deliver it as a web-based service, we expect that the Frontier-enabled version of REMD, called dREMD, will allow researchers to capture the full potential of REMD in a timely and affordable manner from any standard web browser. The specific aims of the project include the development of dREMD software based on existing in-house REMD codes developed by the academic Principal Investigator. The dREMD simulator will be thoroughly tested by comparing its functions with the results of conventional REMD performed on Linux clusters and experimental data. We will then apply dREMD to probe the thermodynamics of ABeta-lipid bilayer interactions. By performing free energy computations, we will study the molecular mechanisms of ABeta monomer and oligomer binding and insertion into cellular bilayers. Our objective will be to determine the ability of ABeta oligomers to perturb or disrupt bilayers. Accomplishment of these specific aims will position Parabon for a Phase II STTR project that will expand the usability features of dREMD and apply it to the study of inhibitors of ABeta-induced disruption of lipid bilayers. The business objectives are to bring to market two offerings: (1) dREMD atop the Parabon Frontier Computation Grid as a pay-per-use service offered to pharmaceutical and biotechnology companies performing structural biology and ligand binding research; (2) dREMD packaged with Frontier Enterprise for in-house delivery of the same capabilities. The biomedical significance of the project is twofold. First, the project is expected to transform the practice of biomolecular simulations by making available to the research community a new and powerful computational tool - dREMD. Being general-purpose, affordable, and easy to use, dREMD will expand the scope of biomolecular simulations to new challenging problems. Second, the project is expected to shed new light on the mechanisms of ABeta peptide cytotoxicity implicated in Alzheimer's disease.