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: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=589340
• 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.

线粒体是一种复杂的、分隔的真核细胞器，在多细胞生物中负责细胞呼吸，即燃烧食物以产生维持生命所需的能量。它由内部基质（Kerbs循环的位置）组成，由两层膜包围：外层是光滑的透水膜，内部是波纹状的高选择性膜。内层膜承载着一系列相互关联的化学反应，这些化学反应利用在吸能电子转移中释放的能量将质子从基质中泵出，并进入膜之间的间隙。这种质子不平衡相当于由于浓度和电梯度的结合而储存的能量。当质子重新进入基质时，这种能量被释放。如果质子通过膜上的“泄漏”重新进入（例如由于解偶联剂），释放的能量就会以热量的形式消散，细胞什么也得不到。为了维持生命（通过产生ATP），质子必须通过ATP合酶内的一个特定通道重新进入，该通道捕获能量以驱动内能反应ADP+Pi- > ATP。提出的研究有两个广泛的目标：(a)使用现代量子化学工具发现线粒体内膜内发生的丰富化学的某些方面，以及(b)使用线粒体系统开发，测试和改进应用量子化学中的新兴方法。关于(a)，将通过计算探索线粒体内膜生物化学的几个方面，例如，跨膜的强电场对膜结合物种的反应性的影响及其与超氧自由基产生的关系，这些超氧自由基涉及加速细胞损伤、退行性疾病和程序性细胞死亡。关于(b)有两个分支。首先是通过在定量构效关系（QSAR）型研究中预测具有已知活性的解偶联剂的性质来改进和扩大最近提出的分子指纹工具的适用性。其次，重建一个巨大的蛋白质，即atp合酶的近似从头算质量电子密度和静电势，其（部分）低分辨率（9 a）结构刚刚发表。这个结构将首先通过同源建模和仔细考虑化学约束来完成。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，精确的几何图形将被用来定义必要的核片段，这些核片段将被组合起来，在从头算的水平上重建整个蛋白质的电子密度和静电势，在几个月的时间里近似地得到难以捉摸的精确结果，原则上，用现在的计算机计算这些结果需要比宇宙年龄更长的时间。