Computer Simulation of Electron and Proton Transfer

描述（由申请人提供）：控制质子易位（PTR）、电子转移（ET）和离子转移的蛋白质，支持活细胞的基本功能，如能量转导、感觉感知、细胞运动、神经传导和信号传导。因此，相应蛋白质的缺陷版本是主要的药物设计目标。膜蛋白结构研究的突破逐渐导致了几种重要类型的质子泵、电子泵和离子通道的结构的阐明，以及关于这些系统运作方式的定性想法。然而，在许多情况下，仍然缺少定量的结构-功能相关性，并且控制这些系统的操作的因素仍然不完全清楚。我们相信，计算机辅助的电荷传输蛋白质的结构-功能相关性是必不可少的，在治疗疾病，涉及这些系统的进一步进展。我们的团队已经开发并验证了一系列强大的策略，用于模拟生物系统中的电子转移，质子转移和离子电流。这些发展包括微观和宏观模拟方法的组合，使人们能够探索被动和主动的电荷传输过程中的短期和长期的时间尺度，并探讨电荷传输蛋白质的结构和它们的生物功能之间的关系。因此，我们终于达到了这样的阶段，我们可以使用现实而实用的方法实际模拟PTR，ET和离子通过蛋白质的传输的时间依赖性，并且我们最终可以量化关键电荷传输系统的作用。在此，我们建议将这一领域的前沿推向以下方向：（i）在关键生物系统的研究中模拟PTR过程和相应的能量学，（ii）通过更明确的模拟验证我们的PTR模型，（iii）通过探索突变的影响，观察到的介电效应的意义和短时弛豫过程的性质，继续我们对反应中心的研究，（iv）研究供体-受体蛋白质复合物的重组能，（v）量化我们对生物离子通道选择性的研究，（vi）继续我们对关键静电问题的研究。公共卫生相关性：控制电子、质子和离子运输的电荷转运蛋白在生物过程中起着至关重要的作用。例如，质子泵调节驱动分子跨膜运输的电化学梯度，而离子通道在神经信号转导和其他关键功能中起着至关重要的作用。破坏这些系统功能的突变与许多疾病相关，相应的蛋白质是治疗干预的主要靶点，并在药物发现工作中发挥核心作用。有缺陷的电荷传输蛋白的先进治疗需要详细了解相应的生物学功能。幸运的是，在阐明膜蛋白的结构的进展提供了主要的相关结构信息。然而，进一步的进展需要定量的结构-功能相关性。我们相信，计算机建模方法可以提供所需的结构-功能的相关性，我们建议推动在质子转移，电子转移和离子转移蛋白质的实际功能建模的前沿。拟议的研究应提供一个更好的理解的分子起源的不同模式的生物电荷传输。这将有助于开发有效的药物，有助于对抗与缺陷电荷转运蛋白相关的疾病。

DESCRIPTION (provided by applicant): Proteins that control proton translocation (PTR), electron transfer (ET) and ion transfer, underpin basic functions of living cells such as energy transduction, sensory perception, cell movement, nerve conduction and signaling. Thus, the defected versions of the corresponding proteins are major drug design targets. The breakthroughs in structural studies of membrane proteins have gradually led to the elucidation of the structures of several important types of proton pumps, electron pumps and ion channels, and to qualitative ideas about the ways these systems operate. Nevertheless, in many cases, a quantitative structure-function correlation is still missing and the factors that control the operation of such systems are still not entirely clear. We believe that computer aided structure-function correlation of charge transport proteins is essential for further advances in treating diseases that involve such systems. Our group has developed and validated a wide range of powerful strategies for modeling electron transfer, proton transfer and ion currents in biological systems. These developments include combinations of microscopic and macroscopic simulation approaches that allow one to explore passive and active charge transport processes in short and long time scales and to explore the relationships between the structure of charge transport proteins and their biological function. Thus, we have finally reached the stage where we can actually simulate the time dependence of PTR, ET and ion transport through proteins, using realistic yet practical methods, and where we can finally quantify the action of key charge transport systems. Here, we propose to push the frontiers of this field in the following directions: (i) Simulating PTR processes and the corresponding energetics in studies of key biological systems, (ii) Validating our PTR models by more explicit simulations, (iii) Continuing our studies of reaction centers by exploring the effects of mutations, the meaning of the observed dielectric effect, and the nature of the short-time relaxation processes, (iv) Studying reorganization energies in donor-acceptor protein complexes, (v) Quantifying our studies of the selectivity of biological ion channels, and (vi) Continuing our studies of key electrostatic problems. PUBLIC HEALTH RELEVANCE: Charge transport proteins that control the transport of electrons, protons and ions, play a crucial role in biological processes. For example, proton pumps regulate the electrochemical gradient that drives the transport of molecules across membranes, while ion channels play a vital role in neural signal transduction and other key functions. Mutations that disrupt the function of such systems are associated with many diseases and the corresponding proteins present major targets for therapeutic intervention as well as playing a central role in drug discovery efforts. Advanced treatments of defective charge transport proteins require a detailed understanding of the corresponding biological functions. Fortunately, the progress in the elucidation of the structure of membrane proteins has provided major relevant structural information. However, further advances require quantitative structure-function correlations. We believe that computer modeling approaches can provide the needed structure-function correlations, and we propose to push the frontiers in modeling the actual function of proton transfer, electron transfer and ion transfer proteins. The proposed studies should provide a better understanding of the molecular origin of the different modes of biological charge transport. This should assist in the development of effective drugs that will help to fight diseases that are associated with defective charge transport proteins.