Quantum Chemical Investigations of the Inner Mitochondrial Membrane Biochemistry

线粒体内膜生物化学的量子化学研究

• 批准号: RGPIN-2015-03731
• 负责人: Matta, Cherif
• 金额: $ 2.04万
• 依托单位: Mount Saint Vincent University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=632396
• 关键词: Quantum; Chemical; Investigations; Inner; Mitochondrial

The mitochondrion is a complex and compartmentalized eukaryotic cell organelle responsible for cellular respiration in a multicellular organism that is, burning foodstuffs to produce the energy necessary for sustaining life. It consists of an inner matrix (the location of the Kerbs cycle) enclosed by two membranes: An outer smooth and permeable membrane, and an inner corrugated and highly selective one. The inner membrane hosts an array of connected chemical reactions that use the energy released in exergonic electron transfers to pump protons out of the matrix and into the gap between the membranes. This proton imbalance is equivalent to stored energy due to the combined concentration and electrical gradients. When protons re-enter the matrix this energy is released. If the protons re-enter through a "leak" in the membrane (e.g. due to uncouplers), the released energy is dissipated as heat and the cell gains nothing. To sustain life (by producing ATP), the protons must re-enter through a specific channel within ATP-synthase which captures the energy to drive the endergonic reaction ADP+Pi--> ATP. The proposed research has two broad goals: (a) Discovering some aspects of the rich chemistry that happens inside the inner mitochondrial membrane using the modern tools of quantum chemistry, and (b) use the mitochondrial systems to develop, test, and improve emerging methodologies in applied quantum chemistry. With regards to (a), several aspects of inner mitochondrial membrane biochemistry will be explored computationally, for example, the effect of the strong electric field across the membrane on the reactivity of membrane-bound species and its relation to the production of the superoxide radicals implicated in accelerating cell damage, degenerative diseases, and programmed cell death. With respect to (b) there are two sub-branches. The first is to improve and broaden the applicability of a recently proposed molecular fingerprinting tool by predicting the properties of uncouplers with known activities in quantitative structure-activity relationship (QSAR)-type studies. Second, the reconstruction of approximate ab initio quality electron density and electrostatic potential of a gigantic protein, namely, ATP-synthase, the (partial) low resolution (9 A) structure of which has just been published. This structure will first be completed through homology modeling and the careful consideration of chemical constraints. To start, the missing amino acids and missing atoms will be added followed by force field geometry optimizations. The refined geometry will then be used to define the necessary kernel fragments that will be combined to reconstruct the electron density and electrostatic potential of the entire protein at an ab initio level, approximating in months elusive exact results that, in principle, should take more than the age of the Universe to calculate with present-day computers.

线粒体是一种复杂而分隔的真核细胞细胞器，负责多细胞生物的细胞呼吸，燃烧食物以产生维持生命所需的能量。它由一个由两个膜包围的内部矩阵（路缘周期的位置）组成：外部光滑且可渗透的膜，以及一个内部波纹和高度选择性的膜。内膜有一系列连接的化学反应，这些反应利用释放的Exerponic电子转移的能量将质子从基质中泵出质子，并进入膜之间的间隙。由于浓度和电梯度的综合，这种质子不平衡等同于存储的能量。当质子重新输入矩阵时，该能量将释放。如果质子通过膜中的“泄漏”重新进入（例如由于解耦合器），则随着热量而释放的能量会消散，细胞却一无所获。为了维持生命（通过产生ATP），质子必须通过ATP合成酶内的特定通道重新进入，该通道捕获了驱动终极反应ADP+PI - > ATP的能量。拟议的研究具有两个广泛的目标：（a）发现使用量子化学的现代工具在内部线粒体内部发生的丰富化学反应的某些方面，（b）使用线粒体系统来开发，测试和改善应用量子化学中的新兴方法。关于（a），例如，将在计算上探索内部线粒体膜生物化学的几个方面，例如，跨膜强场强场对膜结合物种的反应性的影响及其与加速细胞损伤的超氧化物自由基的反应性及其与生产超氧化物自由基的关系。关于（b）有两个子分支。首先是通过预测具有已知活性在定量结构 - 活性关系（QSAR）型研究中具有已知活性的脱钩的特性来改善和扩大最近提出的分子指纹工具的适用性。其次，重建巨大蛋白质的近似质量电子密度和静电电位，即ATP合酶，（部分）低分辨率（9 a）结构的结构刚刚发布。该结构将首先通过同源性建模和仔细考虑化学限制来完成。首先，将添加缺失的氨基酸和缺失的原子，然后进行力场几何优化。然后，精制的几何形状将用于定义必要的内核片段，这些核片段将组合起来，以从头开始重建整个蛋白质的电子密度和静电潜力，在几个月中，原则上应花费超过宇宙的年龄来使用当前的计算机计算出更多的宇宙年龄。