Developing computational methods to determine the thermodynamics of lipid phase coexistence

开发计算方法来确定脂相共存的热力学

• 批准号: 10042128
• 负责人: Alan Grossfield
• 金额: $ 22.02万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042128
• 关键词: Antifungal Agents; Biological; Biology; Case Study; Cells; Cellular Membrane; Cholesterol; Communities; Complex; Complex Variables; Computer Simulation; Computing Methodologies; Coupling; Crowding; Dependence; Detergents; Disease; Environmental Risk Factor; Equilibrium; Free Energy; Grain; Heterogeneity; Length; Lipids; Liquid substance; Measures; Membrane; Membrane Lipids; Membrane Microdomains; Methods; Molecular; Peptides; Performance; Periodicity; Phase; Positioning Attribute; Process; Property; Proteins; Protocols documentation; Role; Sampling; Sodium Chloride; Speed; Sterols; Structure; Surface; System; Techniques; Temperature; Testing; Theoretical model; Thermodynamics; Time; Validation; Work; antimicrobial; base; cold temperature; design; experimental study; improved; in vivo; insight; lipid disorder; melting; membrane model; molecular dynamics; preference; simulation; tool

Project Description Recent years have brought a new appreciation for the role of phase separation in biology, and in particular phase coexistence in the lipid membranes that define the boundaries in and around our cells. Studying this phenomenon using molecular simulation methods remains challenging because of the time- and length-scales involved, and while coarse-grained simulations have reproduced the existence of phase coexistence, to date there are no methods for determining the thermodynamics governing the process. We will develop a new method that will fill this gap, built around the weighted ensemble simulation technique using a contact-based collective variable. We will implement and test a protocol for measuring the free energy to demix 3- component membranes, using coarse-grained simulation with the MARTINI force field as our test suite. In addition, we will implement and validate a new method to couple weighted ensemble with temperature replica exchange, as a way to further speed statistical convergence of the calculations. Finally, we will extend the method to handle the partitioning and aggregation of surface-bound peptides between coexisting phases, using the antifungal lipopeptide fengycin as a test case.

项目描述 近年来，人们对相位分离的作用有了新的认识 生物学，特别是定义的脂质膜中的相位共存 我们的细胞和周围的边界。使用这种现象使用 由于时间和时间，分子模拟方法仍然具有挑战性 涉及的长度尺度，而粗粒模拟已重现 存在相共存的存在，迄今为止没有确定的方法 控制过程的热力学。 我们将开发一种新方法，该方法将填补这一空白，并围绕加权构建 使用基于联系人的集体变量的集合模拟技术。我们将 实施并测试一项协议，以测量Demix 3-的自由能 组件膜，使用马提尼酒的粗粒模拟 力场作为我们的测试套件。此外，我们将实施并验证一个新的 将加权合奏与温度复制式交换的方法，作为一个 进一步加速计算的统计收敛方式。最后，我们会的 扩展方法处理表面结合的分区和聚集的方法 共存阶段之间的肽，使用抗真菌性脂肪肽甲霉素作为 测试案例。