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Dynamical-nonequilibrium simulations: an emerging approach to study time-dependent structural changes in proteins

动态非平衡模拟：研究蛋白质随时间变化的结构变化的新兴方法

基本信息

批准号：
BB/X009831/1
负责人：
Ana Sofia Fernandes De Oliveira
金额：
$ 47.02万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FX009831%2F1
关键词：
Dynamical nonequilibrium simulations emerging approach

项目摘要

Proteins are neither static nor work in isolation in physiological conditions. In fact, it is the opposite; proteins are continuously moving and switching between different conformations. Moreover, changes in the environment can shift the balance between their multitude of conformations. For example, changes in pH and the binding of ions or small molecules to a protein can promote specific structural changes and ultimately determine the protein's macroscopic behaviour. This ability to respond to external changes by fluctuating between conformations is a fascinating feature and is crucial for protein's function and regulation. A detailed description of a protein's conformational rearrangements is essential to understand its working mechanism and function. Even though it is possible to experimentally determine the positions of the atoms in a protein (e.g. using cryogenic electron microscopy or X-ray crystallography), in some cases, the effects of making changes to the protein (e.g. mutations or the binding of ligands and ions) are not obvious. An alternative to experimental approaches is the application of computer simulations. I have been at the forefront of developing and employing computational methods to map structural changes in proteins. For this project, in particular, the approach of combining computer simulations in different conditions (e.g. in the presence and absence of a ligand) is the keystone. This approach permits for a detailed mapping of the time evolution of the structural changes in a protein in response to an external perturbation (e.g. ligand unbinding). The proposed research, undertaken at the University of Bristol, will develop and apply new computational approaches to transform the study of conformational changes in proteins. Three fundamentally different biomolecular systems will be studied during the timeframe of this Fellowship, ranging from soluble enzymes (beta-lactamases) to membrane channels (cystic fibrosis transmembrane conductance regulator (CFTR) channel) and receptors (nicotinic acetylcholine receptors). The diversity of the systems under investigation perfectly highlights the flexibility and general applicability of the computational approaches to be used. Beta-lactamases are bacterial enzymes capable of hydrolysing antibiotics (e.g. penicillin) and are an important cause of resistance to these drugs. The CFTR channel, which sits on the surface of cells, transports chloride and bicarbonate, and its malfunction causes cystic fibrosis. Nicotinic acetylcholine receptors are ion channels widely distributed in the nervous system and are associated with many diseases and conditions, including nicotine and alcohol addiction. In this work, I will map the communication networks connecting functionally important regions within each protein and understand how small molecules and mutations impact those networks. My computational findings will unlock a diversity of interactions that will be explored experimentally by my collaborators, namely Profs Spencer (University of Bristol), Sheppard (University of Bristol), Bermudez (Oxford Brookes University), Sine (Mayo Clinic) and Gallagher (University of Bristol). Their experimental results will feed into my computational models, helping to refine and enhance them. This is a highly collaborative, multidisciplinary project that combines computational (in partnership with Oracle) and experimental expertise, which provides a unique opportunity to expand fundamental knowledge of all three systems' working mechanisms. In the longer term, this knowledge will foretell the properties of newly emerged beta-lactamases mutants, which cause antimicrobial resistance, and inform the design of new therapeutics (e.g. drugs to treat cystic fibrosis, non-opioid drugs for chronic pain, anti-addiction agents and beta-lactamases inhibitors to fight antibiotic resistance).

蛋白质在生理条件下既不是静止的，也不是孤立的。事实上，恰恰相反;蛋白质不断地在不同的构象之间移动和切换。此外，环境的变化可以改变它们众多构象之间的平衡。例如，pH值的变化以及离子或小分子与蛋白质的结合可以促进特定的结构变化，并最终决定蛋白质的宏观行为。这种通过在构象之间波动来响应外部变化的能力是一个迷人的特征，对于蛋白质的功能和调节至关重要。详细描述蛋白质的构象重排对于理解其工作机制和功能至关重要。尽管可以通过实验确定蛋白质中原子的位置（例如使用低温电子显微镜或X射线晶体学），但在某些情况下，对蛋白质进行改变（例如突变或配体和离子的结合）的影响并不明显。实验方法的另一种选择是计算机模拟的应用。我一直处于开发和使用计算方法来绘制蛋白质结构变化的最前沿。对于这个项目，特别是在不同条件下（例如，在存在和不存在配体的情况下）结合计算机模拟的方法是关键。这种方法允许一个详细的映射的时间演变的结构变化的蛋白质响应于外部扰动（例如配体解结合）。这项在布里斯托大学进行的研究将开发和应用新的计算方法来改变蛋白质构象变化的研究。在本奖学金的时间范围内，将研究三种根本不同的生物分子系统，从可溶性酶（β-内酰胺酶）到膜通道（囊性纤维化跨膜传导调节因子（CFTR）通道）和受体（烟碱乙酰胆碱受体）。所调查的系统的多样性完美地突出了所使用的计算方法的灵活性和普遍适用性。β-内酰胺酶是能够水解抗生素（例如青霉素）的细菌酶，并且是对这些药物产生耐药性的重要原因。位于细胞表面的CFTR通道运输氯离子和碳酸氢盐，其功能障碍导致囊性纤维化。尼古丁乙酰胆碱受体是广泛分布在神经系统中的离子通道，与许多疾病和病症有关，包括尼古丁和酒精成瘾。在这项工作中，我将绘制连接每个蛋白质内功能重要区域的通信网络，并了解小分子和突变如何影响这些网络。我的计算发现将解开相互作用的多样性，这些相互作用将由我的合作者进行实验探索，即Spencer教授（布里斯托大学），Sheppard教授（布里斯托大学），Paddez教授（牛津布鲁克斯大学），Sine教授（马约诊所）和Gallagher教授（布里斯托大学）。他们的实验结果将输入我的计算模型，帮助完善和增强它们。这是一个高度协作的多学科项目，结合了计算（与Oracle合作）和实验专业知识，为扩展所有三个系统工作机制的基础知识提供了独特的机会。从长远来看，这一知识将预示新出现的β-内酰胺酶突变体的特性，这些突变体会导致抗生素耐药性，并为新疗法的设计提供信息（例如治疗囊性纤维化的药物，治疗慢性疼痛的非阿片类药物，抗成瘾剂和β-内酰胺酶抑制剂以对抗抗生素耐药性）。

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）

Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations.

DOI：
10.1021/acs.jctc.3c00785
发表时间：
2024-01-09
期刊：
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
影响因子：
5.5
作者：
Oliveira, A. S. F.;Rubio, J.;Noble, C. E. M.;Anderson, J. L. R.;Anders, J.;Mulholland, A. J.
通讯作者：
Mulholland, A. J.

Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease.

DOI：
10.1021/jacsau.3c00185
发表时间：
2023-06-26
期刊：
JACS AU
影响因子：
8
作者：
Chan, H T Henry;Oliveira, A Sofia F;Schofield, Christopher J;Mulholland, Adrian J;Duarte, Fernanda
通讯作者：
Duarte, Fernanda

An expandable, modular de novo protein platform for precision redox engineering.

DOI：
10.1073/pnas.2306046120
发表时间：
2023-08
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Hutchins, George H.;Noble, Claire E. M.;Bunzel, H. Adrian;Williams, Christopher;Dubiel, Paulina;Yadav, Sathish K. N.;Molinaro, Paul M.;Barringer, Rob;Blackburn, Hector;Hardy, Benjamin J.;Parnell, Alice E.;Landau, Charles;Race, Paul R.;Oliver, Thomas A. A.;Koder, Ronald L.;Crump, Matthew P.;Schaffitzel, Christiane;Oliveira, A. Sofia F.;Mulholland, Adrian J.;Anderson, J. L. Ross
通讯作者：
Anderson, J. L. Ross

Heme binding to the SARS-CoV-2 spike glycoprotein.

DOI：
10.1016/j.jbc.2023.105014
发表时间：
2023-08
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Freeman, Samuel L.;Oliveira, A. Sofia F.;Gallio, Andrea E.;Rosa, Annachiara;Simitakou, Maria K.;Arthur, Christopher J.;Mulholland, Adrian J.;Cherepanov, Peter;Raven, Emma L.
通讯作者：
Raven, Emma L.

Molecular mechanisms of chaperone-directed protein folding: Insights from atomistic simulations.

伴侣定向蛋白质折叠的分子机制：原子模拟的见解。