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Molecular Dynamics and EPR spectroscopy on lipid bilayers: new approaches to study biological membranes

脂双层分子动力学和 EPR 光谱：研究生物膜的新方法

基本信息

批准号：
EP/L001322/1
负责人：
Vasily Oganesyan
金额：
$ 59.16万
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FL001322%2F1
关键词：
Molecular Dynamics EPR spectroscopy lipid

项目摘要

Lipid bilayers are the main building blocks of biological membranes. They play a key part in many important biological mechanisms in membranes such as providing living cells with energy, organising and regulating enzyme activities, facilitating the transduction of information and even the supply of substrates for biosynthesis and for signalling molecules. It is widely accepted that membranes do not form homogeneous fluid lipid phases but, in contrast, lipids are organised into phase separated dynamical domains depending on various conditions. Knowledge of molecular interactions, thermodynamics and system composition effects are crucial for understanding the role which different lipids play in vital life processes in biological membranes. This knowledge is also important for the design of drug delivery systems based on liposomes (artificial vesicles composed of lipid bilayers). An example would be "trigger release liposomes" where temperature sensitive liposomes could be engineered in a way to have phase separated domains to release their content upon trigger.Of the biophysical techniques now being brought to bear on studies of membranes Electron Paramagnetic Resonance (EPR) of nitroxide spin probes was the first to provide information about mobility and ordering in lipid membranes and lipid bilayer systems. Spin probes, specially designed chemical agents that carry a stable unpaired electron, can be introduced within complex partially ordered molecular systems in order to report on the order and dynamics of surrounding molecules. They can probe different depths / parts of the bilayer and also be attached to embedded peptides and proteins. Because an electron has a magnetic moment it can interact with an external magnetic field. EPR measures this interaction in the form of spectral line shape. The orientation of the spin label to the magnetic field has a dramatic effect on this line shape and therefore molecular mobility, dynamics and distribution can be studied. EPR is a technique that acts as a snapshot of very fast molecular motions and can resolve molecular re-orientational dynamics of the introduced spin probe over times shorter than a billionth of a second. However, the analysis of the rich and complex in information EPR lineshape requires full computer simulation. Current approaches rely on simplified parametrised models of motion and require fitting of EPR spectra with multiple adjustable parameters. Such approaches in many cases do not provide an unambiguous interpretation of the spectra preventing definite conclusions about motion and order in multi-component lipid bilayers to be reached. The last decade has seen radical improvement in the molecular modelling of complex molecular and bio-molecular systems including lipid bilayers using Molecular Dynamics (MD) simulation techniques. MD simulations are now much faster and more accurate allowing researchers to predict complex molecular phenomena using actual structures.This project will bring together MD and EPR and will attempt for the first time simulation of EPR spectra of biological membranes directly from the results of MD. The advantage of such an approach is twofold. Firstly, it will provide the improvement and will facilitate the interpretation of EPR of biological membranes. Secondly, our MD-EPR methodology will serve as a test bed for advanced computational models for lipid bilayers simulations.We will use the unique combination of expertises from UEA in both EPR and atomistic MD simulations of spin labelled bio-molecules and coarse-grained simulations on large scale systems provided by Durham.We will use a novel MD-EPR methodology to address the key problems of understanding molecular interactions, thermodynamics and system composition effects on the formation and dynamics of lipid domains, the organisation and dynamics of lipids around trans-membrane proteins, and the role of cholesterol as a lipid bilayer stabiliser.

脂质双层是生物膜的主要组成部分。它们在膜中的许多重要生物机制中起关键作用，例如为活细胞提供能量，组织和调节酶活性，促进信息的转导，甚至为生物合成和信号分子提供底物。人们普遍认为，膜不形成均匀的流体脂质相，但相反，脂质根据各种条件被组织成相分离的动力学域。分子相互作用，热力学和系统组成的影响的知识是至关重要的了解不同的脂质在生物膜中的重要生命过程中发挥的作用。这些知识对于基于脂质体（由脂质双层组成的人工囊泡）的药物递送系统的设计也很重要。一个例子是“触发释放脂质体”，其中温度敏感的脂质体可以被设计成具有相分离的结构域，以在触发时释放其内容物。在现在被用于研究膜的生物物理技术中，氮氧自旋探针的电子顺磁共振（EPR）是第一个提供关于脂质膜和脂质双层系统中的流动性和有序性的信息的技术。自旋探针是专门设计的携带稳定未配对电子的化学试剂，可以引入复杂的部分有序分子系统中，以报告周围分子的顺序和动力学。它们可以探测双层的不同深度/部分，也可以附着在嵌入的肽和蛋白质上。因为电子具有磁矩，所以它可以与外部磁场相互作用。EPR以谱线形状的形式测量这种相互作用。自旋标记对磁场的取向对这种线形有显著的影响，因此可以研究分子的迁移率、动力学和分布。EPR是一种作为非常快的分子运动的快照的技术，并且可以在短于十亿分之一秒的时间内解析引入的自旋探针的分子重新取向动力学。然而，分析信息量丰富而复杂的EPR谱线形态，需要进行充分的计算机模拟。目前的方法依赖于简化的参数化运动模型，并需要与多个可调参数的EPR谱拟合。在许多情况下，这种方法不提供明确的解释，防止明确的结论，在多组分脂质双层的运动和秩序的光谱要达到。在过去的十年中，已经看到了根本性的改进，在分子建模的复杂分子和生物分子系统，包括脂质双层使用分子动力学（MD）模拟技术。MD模拟现在更快，更准确，使研究人员能够预测复杂的分子现象，使用实际的结构。该项目将把MD和EPR结合起来，并将首次尝试直接从MD的结果模拟生物膜的EPR光谱。这种做法的好处是双重的。首先，它将提供改进，并将有助于生物膜的EPR的解释。第二，我们的MD-EPR方法将作为先进的脂双层模拟计算模型的测试平台。我们将使用UEA在自旋标记生物分子的EPR和原子MD模拟以及达勒姆提供的大规模系统的粗粒度模拟方面的独特组合。我们将使用一种新的MD-EPR方法来解决理解分子相互作用的关键问题，热力学和系统组成对脂质结构域的形成和动力学的影响，跨膜蛋白周围脂质的组织和动力学，以及胆固醇作为脂质双层稳定剂的作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Application of Molecular Modelling and EPR Spectroscopy to Lipid Membranes - a Combined Approach

分子建模和 EPR 光谱在脂膜中的应用 - 组合方法

DOI：
发表时间：
2016
期刊：
Armenian Journal of Physics
影响因子：
0
作者：
Catte A.
通讯作者：
Catte A.

Electron Paramagnetic Resonance - Volume 24

电子顺磁共振 - 第 24 卷

DOI：
10.1039/9781782620280-00032
发表时间：
2014
期刊：
影响因子：
0
作者：
Oganesyan V
通讯作者：
Oganesyan V

EPR spectroscopy and molecular dynamics modelling: a combined approach to study liquid crystals

DOI：
10.1080/02678292.2018.1508767
发表时间：
2018-12-08
期刊：
LIQUID CRYSTALS
影响因子：
2.2
作者：
Oganesyan，Vasily S.
通讯作者：
Oganesyan，Vasily S.

Direct Prediction of EPR Spectra from Lipid Bilayers: Understanding Structure and Dynamics in Biological Membranes.

DOI：
10.1002/cphc.201800386
发表时间：
2018-09-05
期刊：
Chemphyschem : a European journal of chemical physics and physical chemistry
影响因子：
0
作者：
Catte A;White GF;Wilson MR;Oganesyan VS
通讯作者：
Oganesyan VS

All-atom molecular dynamics simulations of spin labelled double and single-strand DNA for EPR studies.