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.

线粒体是一个复杂的、分区的真核细胞细胞器，负责多细胞有机体的细胞呼吸，即燃烧食物以产生维持生命所需的能量。它由两层膜包围的内部基质(路缘循环的位置)组成：外部光滑且可渗透的膜，以及内波纹且具有高度选择性的膜。内膜包含一系列相互连接的化学反应，这些化学反应利用电子传递过程中释放的能量，将质子从基质中抽出，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组合而储存的能量。当质子重新进入母体时，这种能量就会释放出来。如果质子通过膜中的“泄漏”重新进入(例如，由于解偶联器)，释放的能量以热的形式消散，电池什么也得不到。为了维持生命(通过产生ATP)，质子必须通过ATP合成酶中的特定通道重新进入，该通道捕获能量以驱动ADP+PI-&&gt；ATP反应。拟议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)使用线粒体系统来开发、测试和改进应用量子化学中的新兴方法。关于(A)，我们将通过计算探讨线粒体膜内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，以及它与加速细胞损伤、退行性疾病和程序性细胞死亡所涉及的超氧阴离子自由基的产生的关系。关于(B)项，有两个分支机构。第一种是通过在定量结构-活性关系(QSAR)类型的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分析工具的适用性。第二，重建一个巨型蛋白质的近似从头算质量电子密度和静电势，即刚刚公布的(部分)低分辨(9A)结构的ATP合成酶。这种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，然后是力场几何优化。然后，精细的几何结构将被用来定义必要的核碎片，这些碎片将被组合在一起，在从头开始的水平上重建整个蛋白质的电子密度和静电势，在几个月内近似难以捉摸的准确结果，原则上，用现在的计算机计算应该需要比宇宙年龄更长的时间。