Nano to Meso and Back Again: Capturing and Exploiting Dynamic Heterogeneities in Biological Membranes via Large Scale Simulations

纳米到介观再返回：通过大规模模拟捕获和利用生物膜中的动态异质性

• 批准号: BB/R00126X/1
• 负责人: Mark Sansom
• 金额: $ 44.93万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR00126X%2F1
• 关键词: Nano; Meso; Back; Again; Capturing

Membranes are of fundamental importance to biology: they form the 'surrounding walls' of all cells, and control the flow of materials and information into and out of cells. The proteins of membranes are embedded in a lipid bilayer, which is an oil-like film separating the cellular contents from its watery external environment. These membrane proteins are responsible for many key biological functions, including communication between cells, and consequently are targets for many drugs, including some antibiotics. However, membranes are more than a simple 'sum of their parts'. Rather, they are complex and dynamic assemblies of proteins and lipids, and their biological functions are emergent properties of the membrane system as a whole. The overall aim of this proposal is to develop methods to understand how the various components of membranes are dynamically organized so as to carry out their biological functions.Computer simulations of the interacting molecules (proteins and lipids) which make up cell membranes may be used to study their dynamic behaviour and organization. Simulation studies to date have been limited to the very small (nano)scale, and have focused on e.g. the interactions of single membrane proteins with immediately neighbouring lipid molecules. However, larger scale simulations are needed to address (sub)cellular scales of the dynamic organization of cell membranes. These larger scale simulations will enable direct comparison of predictions emerging from simulations with experimental observations. We will develop larger scale simulations using 'meso' scale models which can be built using the outcomes of smaller scale models and simulations which have already been successfully employed to study isolated membrane proteins.We will use advanced computer simulations, benefiting from UK investment in national supercomputing facilities, to:1. Develop biologically realistic models of dynamic spatial heterogeneities in cell membranes; and2. Link smaller scale (coarse-grained) and larger scale (meso) models with experimental data in an integrated approach allowing us to bridge between structural and cellular studies of membranes. Thus, the overall outcome of these studies will be a powerful new computer simulation method for biological membranes, which will have applications relevant to the pharmaceutical and biotechnology sectors.

膜对生物学至关重要：它们形成了所有细胞的“周围壁”，并控制材料和信息流入和流出细胞的流动。膜的蛋白质嵌入到脂质双层中，这是一种油状膜，将细胞含量与水状外部环境区分开。这些膜蛋白负责许多关键的生物学功能，包括细胞之间的通信，因此是许多药物（包括某些抗生素）的靶标。但是，膜不仅仅是简单的“部分总和”。相反，它们是蛋白质和脂质的复杂和动态组件，它们的生物学功能是整个膜系统的新兴特性。该提案的总体目的是开发方法，以了解如何动态组织膜的各种成分，以执行其生物学功能。computer模拟相互作用的分子（蛋白质和脂质），这些分子（蛋白质和脂质）可能会用于研究其动态行为和组织。迄今为止的模拟研究仅限于非常小的（NANO）量表，并专注于例如单个膜蛋白与立即相邻的脂质分子的相互作用。但是，需要更大的模拟来解决细胞膜动态组织的（子）细胞尺度。这些较大的规模仿真将能够直接比较与实验观察结果一起从模拟中出现的预测。我们将使用“ MESO”量表模型开发较大的模拟，这些模型可以使用较小规模的模型和模拟的结果来构建，这些模型和模拟已经成功地研究了孤立的膜蛋白。我们将使用先进的计算机模拟，从而受益于英国在国家超级计算设施中的投资，to：1。开发细胞膜动态空间异质性的生物学现实模型；和2。将较小的规模（粗粒）和较大规模（MESO）模型与实验数据联系起来，以综合方法，使我们能够在膜的结构和细胞研究之间桥接。因此，这些研究的总体结果将是一种针对生物膜的强大新计算机模拟方法，该方法将具有与药物和生物技术领域相关的应用。

项目成果

The energetics and ion coupling of cholesterol transport through Patched1.

• DOI: 10.1126/sciadv.adh1609
• 发表时间: 2023-08-25
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Ansell, T. Bertie;Corey, Robin A.;Viti, Lucrezia Vittoria;Kinnebrew, Maia;Rohatgi, Rajat;Siebold, Christian;Sansom, Mark S. P.
• 通讯作者: Sansom, Mark S. P.

Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR

多尺度分子动力学模拟、马尔可夫态模型和 NMR 揭示了 a-突触核蛋白的膜相互作用

• DOI: 10.1101/2020.06.18.156216
• 发表时间: 2020
• 作者: Amos S

Coarse-Grained Simulations Suggest the Epsin N-Terminal Homology Domain Can Sense Membrane Curvature without Its Terminal Amphipathic Helix.

• DOI: 10.1021/acsnano.0c05960
• 发表时间: 2020-12-22
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Belessiotis-Richards A;Higgins SG;Sansom MSP;Alexander-Katz A;Stevens MM
• 通讯作者: Stevens MM

The Energetics and Ion Coupling of Cholesterol Transport Through Patched1

• DOI: 10.1101/2023.02.14.528445
• 发表时间: 2023-02
• 期刊: bioRxiv
• 作者: T. Ansell;R. Corey;Lucrezia Vittoria Viti;M. Kinnebrew;R. Rohatgi;C. Siebold;M. Sansom

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.

• DOI: 10.1021/acs.jctc.1c00547
• 发表时间: 2021-10-12
• 期刊: Journal of chemical theory and computation
• 影响因子: 5.5
• 作者: Ansell TB;Curran L;Horrell MR;Pipatpolkai T;Letham SC;Song W;Siebold C;Stansfeld PJ;Sansom MSP;Corey RA
• 通讯作者: Corey RA