Theoretical Investigations of some Outstanding Problems in Biophysical Chemistry

生物物理化学若干突出问题的理论研究

• 批准号: RGPIN-2022-04842
• 负责人: Matta, Cherif
• 金额: $ 2.62万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748561
• 关键词: Theoretical; Investigations; some; Outstanding; Problems

The mitochondrion is responsible for the conversion of most of the energy in the foodstuff to the universal metabolic fuel par excellence, ATP (adenosine 5'-triphosphate). Various metabolites eventually make their way inside the mitochondrial matrix where they are oxidized delivering electrons to be channeled through the "electron transport chain" (ETC) inside the inner mitochondrial membrane (IMM). The energy released from the reactions of the ETC is used to pump protons in the mitochondrial inter-membrane gap creating and maintaining a chemical and an electrical potential gradient. Protons going back downhill, through ATP synthase's channel, release this energy which is captured by ATP synthase by adding a third phosphate group to ADP to form ATP. We have recently discovered that ATP synthase must dissipate a minimum energy (> kBTln2) every time it selects a proton to go through its channel. This is called "Landauer's principle". We have also found that the enzyme, isolated from 5 different species, have consistent electrical properties. For example, the protein's intrinsic electrostatic potential gives rise to a potential difference between the entry point of the protons (on the gap side) and their exit point (on the matrix side). This voltage reinforce one due to the proton gradient and contribute an energy term that is of the same order of magnitude but opposite in sign to that which needs to be dissipated. Hence, the enzyme has evolved to pay for its own operation, so to speak. This proposal will explore these recent but preliminary findings in much greater depth. Using quantum chemistry, we will also study how the strong electric field that crosses the IMM influences the thermodynamics and kinetics of the ETC reactions. One particular reaction of interest is that of the generation of reactive oxygen species. We propose a feedback mechanism of control of the IMM potential whereby the system reacts à la "Le Chatelier's" to maintain homeostasis. A second line of research will inquire into the possible role of thermodynamics as a prebiotic driver of (Darwinian) natural selection of nucleic acids. Specifically, we wish to understand why the nucleic acids we have today are in the present-day particular form and not in any of the closely related and accessible alternative forms? Is it a matter of free energy or are there other factors? Finally, our interest in questions related to origins of life led us to the century-old problem of Diffuse Interstellar Bands (DIBs). These are absorption lines due to dust clouds along the sight-lines of many stars. Our recent work has identified 4 novel groups of related DIB lines (4 families), each of which may well originate from a unique chemical source (a molecule, a complex ion, an atomic cluster, ...). A combination of statistics and state-of-the-art ab initio spectral calculations will shed light on possible chemical sources of these new DIB families.

线粒体负责将食物中的大部分能量转化为通用的代谢燃料，即ATP（5'-三磷酸腺苷）。各种代谢物最终进入线粒体基质，在那里它们被氧化，传递电子，通过线粒体内膜（IMM）内的“电子传递链”（ETC）。ETC反应释放的能量被用来将质子泵入线粒体膜间隙，产生并维持化学和电势梯度。质子回到山下，通过ATP合酶的通道，释放能量被ATP合酶捕获，通过在ADP上添加第三个磷酸基形成ATP。我们最近发现，ATP合酶每次选择一个质子通过其通道时，必须耗散一个最小能量（> kBTln2）。这就是所谓的“兰道尔原理”。我们还发现，从5种不同的物种中分离出来的酶具有一致的电学性质。例如，蛋白质的固有静电势导致质子的入口点（在间隙一侧）和它们的出口点（在基质一侧）之间的电位差。由于质子梯度，这个电压增强了一个，并贡献了一个能量项，它与需要耗散的能量项具有相同的数量级，但符号相反。因此，可以说，这种酶已经进化到可以为自己的运作买单了。本建议将更深入地探讨这些最近但初步的发现。利用量子化学，我们还将研究穿过IMM的强电场如何影响ETC反应的热力学和动力学。一个特别有趣的反应是活性氧的生成。我们提出了一种控制IMM电位的反馈机制，即系统根据“勒夏特列”反应来维持内稳态。第二项研究将探讨热力学作为（达尔文的）核酸自然选择的益生元驱动因素的可能作用。具体来说，我们希望理解为什么我们今天拥有的核酸是今天的特定形式，而不是任何密切相关的，可获得的替代形式？这是自由能的问题还是有其他因素？最后，我们对生命起源相关问题的兴趣将我们引向了一个世纪之久的问题——弥漫星际带（DIBs）。这些是由于许多恒星的视线上的尘埃云所产生的吸收线。我们最近的工作已经确定了4个新的相关DIB系（4个家族），每一个都可能来自一个独特的化学来源（一个分子，一个复合离子，一个原子簇，…）。统计数据和最先进的从头算光谱计算相结合，将揭示这些新DIB家族可能的化学来源。