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Combined quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations: a feasibility study

组合量子力学/分子力学 (QM/MM) 蒙特卡罗自由能模拟：可行性研究

基本信息

批准号：
EP/E022197/1
负责人：
Adrian Mulholland
金额：
$ 7.56万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FE022197%2F1
关键词：
Combined quantum mechanics molecular QM

项目摘要

Despite the advances of science, millions of people still die every year from incurable diseases. Unfortunately, the costs of drug development are so high that the focus of medicinal research is into profitable Western diseases. To reduce the costs of developing new medicinal drugs, we would like to be able to use computers to model how a potential drug works within the body, and to use this knowledge to design new and better drugs. Building computational models like this is challenging, requiring a delicate balance between putting enough detail into the model to get realistic behaviour, and making the model as simple as possible so that it doesn't take too long to run the calculations. Until now, the majority of models used have been very simple, modelling the atoms of a drug as balls on springs. By treating the atoms as solid balls, the models neglect the atom's most chemically important part, namely the electrons. This is a severe oversight, as it is the interactions of electrons that determine whether the drug could dissolve in your blood, work its way into your cells, and bind to, and thus neutralize, the proteins of any attacking bacteria or virus. It is possible to model electrons in molecules using quantum mechanics. However, to model the entire protein/drug system using quantum mechanics would be too computationally expensive. We propose to research the use of quantum mechanics to model just the electrons that are part of, and near to, the drug molecule. The rest of the protein can still be treated by simple ball and springs models to make the calculations possible. The new methods we will develop add important extra detail, making them more realistic and better able to model how drugs interact. At the same time, this combined approach should mean that the calculations are practical to do. What makes our planned work different is that it will involve the development of a mixed model specifically tailored for medicinal drug design. Creating a mixed model for this use will require that significant challenges are overcome, and that new ways are developed to handle the interactions between the quantum mechanics part of the model with the ball on springs part.

尽管科学取得了进步，但每年仍有数百万人死于不治之症。不幸的是，药物开发的成本如此之高，以至于医学研究的重点是有利可图的西方疾病。为了降低开发新药物的成本，我们希望能够使用计算机来模拟潜在药物在体内的作用方式，并利用这些知识来设计新的更好的药物。构建这样的计算模型具有挑战性，需要在模型中添加足够的细节以获得真实的行为与使模型尽可能简单以便运行计算不会花费太长时间之间保持微妙的平衡。到目前为止，使用的大多数模型都非常简单，将药物原子建模为弹簧上的球。通过将原子视为实心球，模型忽略了原子在化学上最重要的部分，即电子。这是一个严重的疏忽，因为电子的相互作用决定了药物是否可以溶解在您的血液中，进入您的细胞，并与任何攻击性细菌或病毒的蛋白质结合，从而中和它们。可以使用量子力学对分子中的电子进行建模。然而，使用量子力学对整个蛋白质/药物系统进行建模的计算成本太高。我们建议研究使用量子力学来模拟药物分子一部分和附近的电子。蛋白质的其余部分仍然可以通过简单的球和弹簧模型进行处理，以使计算成为可能。我们将开发的新方法添加了重要的额外细节，使它们更加现实并且能够更好地模拟药物如何相互作用。同时，这种组合方法应该意味着计算是可行的。我们计划的工作的不同之处在于，它将涉及开发专门为药物设计量身定制的混合模型。为此用途创建混合模型需要克服重大挑战，并且需要开发新方法来处理模型的量子力学部分与弹簧部分的球之间的相互作用。

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）

Entropy of Simulated Liquids Using Multiscale Cell Correlation.

DOI：
10.3390/e21080750
发表时间：
2019-07-31
期刊：
Entropy (Basel, Switzerland)
影响因子：
0
作者：
Ali HS;Higham J;Henchman RH
通讯作者：
Henchman RH

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

New methods: general discussion.

新方法：一般性讨论。