Incorporating MM Polarization in hybrid QM/MM calculations

将 MM 极化纳入混合 QM/MM 计算

• 批准号: BB/G000719/1
• 负责人: Christopher Reynolds
• 金额: $ 12.97万
• 依托单位: University of Essex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG000719%2F1
• 关键词: Incorporating; MM; Polarization; hybrid; QM

Computer simulation now plays a major role in understanding biological systems and in the design of molecules as new materials and new pharmaceuticals. In cases where it is important to study the molecules in atomic-level detail so that the distribution of electrons within the molecules can be understood, then quantum mechanics is the method of choice. In cases where the environment surrounding these molecules affects this distribution of electrons, then hybrid quantum mechanical / molecular mechanics (QM/MM) methods are used. The QM means that the molecule of interest can be studied accurately; the MM means that the environment that this molecule is in can also be taken into account, albeit at a lower level of accuracy. Within the MM part of these calculations, it is assumed that the electrons have a fixed distribution that does not change in response to the QM region of interest. Here we propose to introduce new computer methods so that the polarization of the electron distribution within the MM region can be taken into account. A simple illustration should highlight the importance of this effect. When a drug binds to an enzyme, the structure of both the drug and the enzyme must flex to accommodate each other. A similar accommodation is occurring in the spatial distribution of the electrons. Ignoring this redistribution (i.e. polarization) is therefore rather like attempting to put on a glove that is almost frozen solid. A significant part of the project will involve work to ensure that these methods can be readily used by other scientists. Applications of this new method will enable increased atomic and molecular level understanding of biological processes. The scientists that will benefit will not only include theoreticians but also enzymologists, those involved in drug design, bioinorganic chemists, photochemists, material scientists, plant scientists, spectroscopists, and those involved in biotechnology software companies.

计算机模拟现在在理解生物系统和设计分子作为新材料和新药物方面发挥着重要作用。在某些情况下，重要的是在原子水平上研究分子的细节，以便可以理解分子内电子的分布，那么量子力学是选择的方法。在这些分子周围的环境影响电子的这种分布的情况下，则使用混合量子力学/分子力学（QM/MM）方法。QM意味着可以准确地研究目标分子; MM意味着也可以考虑该分子所处的环境，尽管准确度较低。在这些计算的MM部分中，假设电子具有不响应于感兴趣的QM区域而改变的固定分布。在这里，我们建议引入新的计算机方法，使MM区域内的电子分布的极化可以考虑在内。一个简单的例子应该强调这种效果的重要性。当药物与酶结合时，药物和酶的结构必须弯曲以相互适应。在电子的空间分布中也发生了类似的调节。因此，忽视这种再分配（即极化）就像试图戴上一只几乎冻硬的手套。该项目的一个重要部分将涉及确保其他科学家可以随时使用这些方法的工作。这种新方法的应用将使生物过程的原子和分子水平的理解增加。受益的科学家不仅包括理论家，还包括酶学家、药物设计人员、生物无机化学家、光化学家、材料科学家、植物科学家、光谱学家以及生物技术软件公司的人员。

项目成果

The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.

• DOI: 10.1016/j.cell.2016.05.023
• 发表时间: 2016-06-16
• 期刊: Cell
• 影响因子: 64.5
• 作者: Wootten D;Reynolds CA;Smith KJ;Mobarec JC;Koole C;Savage EE;Pabreja K;Simms J;Sridhar R;Furness SGB;Liu M;Thompson PE;Miller LJ;Christopoulos A;Sexton PM
• 通讯作者: Sexton PM

Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor.

• DOI: 10.1016/j.bcp.2016.08.015
• 发表时间: 2016-10-15
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Wootten, Denise;Reynolds, Christopher A.;Smith, Kevin J.;Mobarec, Juan C.;Furness, Sebastian G. B.;Miller, Laurence J.;Christopoulos, Arthur;Sexton, Patrick M.
• 通讯作者: Sexton, Patrick M.