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.

该酶负责将食物中的大部分能量转化为卓越的通用代谢燃料ATP（腺苷5 '-三磷酸）。各种代谢物最终进入线粒体基质，在线粒体基质中它们被氧化，传递电子以通过线粒体内膜（IMM）内的“电子传递链”（ETC）进行通道传输。从ETC的反应释放的能量用于在线粒体膜间间隙中泵送质子，从而产生并维持化学和电势梯度。质子通过ATP合酶的通道返回下坡，释放能量，ATP合酶通过将第三个磷酸基团添加到ADP形成ATP来捕获能量。我们最近发现，ATP合酶每次选择一个质子通过它的通道时，必须耗散最小能量（> kBTln 2）。这就是所谓的“Landauer原理”。我们还发现，从5个不同物种中分离的酶具有一致的电特性。例如，蛋白质的固有静电势在质子的进入点（在差距侧）和它们的离开点（在基质侧）之间产生电势差。该电压由于质子梯度而增强一个，并且贡献与需要耗散的能量具有相同数量级但符号相反的能量项。因此，可以说，酶已经进化到为自己的运作买单。本提案将更深入地探讨这些最近的初步调查结果。使用量子化学，我们还将研究如何穿过IMM的强电场影响ETC反应的热力学和动力学。感兴趣的一个特定反应是产生活性氧物质的反应。我们提出了一个反馈机制的IMM潜在的控制，使系统的反应à la“勒Chatelier的”，以保持体内平衡。第二条研究路线将探讨热力学作为核酸（达尔文）自然选择的益生驱动力的可能作用。具体地说，我们希望了解为什么我们今天所拥有的核酸是目前的特定形式，而不是任何密切相关和可获得的替代形式？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有百年历史的弥散星际带（DIB）问题。这些吸收线是由于尘埃云沿着许多恒星的视线。我们最近的工作已经确定了4组新的相关DIB线（4个家庭），其中每一个都可能来自一个独特的化学来源（分子，复合离子，原子簇等）。结合统计和国家的最先进的从头算光谱计算将揭示这些新的DIB家族的可能的化学来源。