Multiscale Simulations of Biological Systems and Processes

项目摘要 在过去的几十年里，对人类健康的分子基础的理解取得了进展， 太棒了然而，我们在结构信息的转换方面远远落后， 将蛋白质序列转化为相应的功能。这方面的进展可以大大推进， 多尺度计算机模拟，可以处理不同的系统，增加了复杂性。在这个 阶段，我们准备将这些方法应用于其理解与重要医学相关的系统， 问题，包括酶的设计，耐药性和质子和离子的转运机制的研究， 从而阐明了生命系统中催化控制、生物能量学和能量转换的基础。我们 建议的协调方向如下。 A.1酶对生化过程的控制：许多疾病可以通过开发药物来控制 阻止酶在重要生物途径中的作用。在结构和 生物化学研究尚未导致对酶反应的能量学的定量理解。 进一步的定量进展需要可靠的工具来研究酶的结构-功能相关性。我们 这方面的进展导致了模拟酶的有效多尺度方法的发展 催化作用在这个阶段，重要的是利用我们的进步，同时在以下方面取得进展 方向：（a）量化计算机辅助酶设计：（i）再现观察到的催化作用， 关键设计酶的EVB和其他多尺度方法。(ii)使用我们的多尺度方法， 酶设计项目，包括改变混杂酶的作用，提高可用的设计师， 帮助设计新的酶。在探索了我们方法的预测能力之后， 我们将与参与酶设计实验的研究小组合作使用它们。（B） 继续推进定量计算方法，包括：（i）使用我们的PD QM（ai）/MM， 评估从头算自由能表面的酶反应;（ii）使用PD方法自动 改进EVB表面以探索长距离突变效应和催化景观;以及（iii） 量化折叠和稳定性之间的关系。(c)探索定向进化的催化作用 并确定它与自然进化的关系。(d)对重要的酶类进行研究 反应. (e)我们的发现与医学问题（包括耐药性）的关系将被探讨。 A.2复杂生物系统的能量学和功能的多尺度建模： 引导电子、质子和离子的运输，支持活细胞的基本功能。例如，质子 泵调节驱动分子跨膜运输的电化学梯度。 同样，离子通道在神经信号转导和其他功能中起着至关重要的作用。突变会破坏 这些系统的作用与许多毁灭性疾病有关。因此，这些蛋白质 它是治疗干预的主要目标，并在药物发现工作中发挥核心作用。尽管最近 在质子泵、离子通道和相关系统的研究中， 许多情况下，定量结构-功能相关性仍然缺失。因此，至关重要的是， 使用计算机模拟方法改进和应用定量结构-功能相关性。过去 我们已经在涉及质子运输的系统中，在将结构转换为功能方面取得了重大进展 (PTR)和电荷传输。这是通过开发微观和粗粒度（CG）方法完成的 包括多尺度方法，使我们能够探索非常长的时间过程。我们的多尺度模型 使我们能够在以下方向取得进展：（a）模拟时间演变， 蛋白质中的PTR使用现实而实用的方法，在那里我们可以量化关键质子的作用， （i）利用我们初步取得的进展，继续 探索氧化还原偶联的细胞色素c氧化酶（CcO）的门控机制， ·定义的通道，其中PTR的激活障碍是已知的，包括在ba 3型和相关系统中。 (ii)利用我们最近在模拟FO-ATPase中pH梯度转换方面的突破 系统的矢量旋转，并获得有关质子路径的更好的理解。(iii)探索 Hv 1中的电压激活PTR。(iv)继续我们对细菌视紫红质（bR）的PTR的研究。(v)利用 我们在膜电位的现实建模方面的进展，以解释这些之间的观察到的关系， 电位和CcO中PT步骤的路径。(b)利用我们在电压建模方面的最新进展 激活离子通道，以推进以下项目：（i）量化电极之间的相互作用 电位和电压激活过程中的蛋白质/膜景观，（ii）再现门控 电流以及随后的离子电流和选择性。(iii)验证我们的模拟方法。(c)建模 通过我们的多尺度方法来研究运输者的行为。(iv)考虑到我们的发现与 各种疾病。

Project Summary The advance in understanding of the molecular basis of human health in the past few decades has been tremendous. However, we are far behind in terms of the conversion of the information about structures and sequence of proteins into the corresponding functions. The progress on this front can be greatly advanced by multiscale computer simulations that can treat different systems with increased level of complexity. At this stage we are ready to apply such methods to systems whose understanding are relevant to important medical problems, including studies of enzyme design, drug resistance and transport mechanism of protons and ions, thereby elucidating the basis of catalytic control, bioenergetics and energy transduction in living systems. Our proposed concerted directions are listed below. A.1 Control of Biochemical Processes by Enzymes: Many diseases can be controlled by developing drugs that block the action of enzymes in crucial biological pathways. The great advances in structural and biochemical studies have not yet led to a quantitative understanding of the energetics of enzymatic reactions. Further quantitative progress requires reliable tools for the structure-function correlation of enzymes. Our advances in this direction have led to the development of effective multiscale methods for simulating enzyme catalysis. At this stage it is important to exploit our advances and to progress simultaneously in the following directions: (a) Quantifying computer-aided enzyme design by: (i) reproducing the observed catalytic effects of key designer enzymes by the EVB and other multiscale approaches. (ii) Using our multiscale approaches in enzyme design projects, including changing the action of promiscuous enzymes, improving available designer enzymes and helping in the design of new enzymes. After exploring the predictive power of our approaches, we will use them in collaboration with research groups that are involved in enzyme design experiments. (b) Continuing to advance quantitative computational methods, including: (i) using our PD QM(ai)/MM in evaluating the ab initio free energy surfaces of enzymatic reactions; (ii) using the PD approach to automatically refine EVB surfaces for exploring long distance mutational effects and catalytic landscapes; and (iii) Quantifying the relationship between folding and stability. (c) Exploring the catalytic effect of directed evolution and determining its relationship to natural evolution. (d) Conducting studies of important classes of enzymatic reactions. (e) The relations of our finding to medical problems (including drug resistance) will be explored. A.2 Multiscale Modeling of the energetics and functions of complex biological systems: Proteins that guide the transport of electrons, protons and ions underpin basic functions of living cells. For example, proton pumps regulate the electrochemical gradient that drives the transport of molecules across membranes. Similarly, ion channels play a vital role in neural signal transduction and other functions. Mutations that disrupt the action of such systems are associated with many devastating diseases. Therefore these proteins present major targets for therapeutic intervention and play a central role in drug discovery efforts. Despite recent structural and biochemical progress in studies of proton pumps, ion channels and related systems, there are many cases where a quantitative structure-function correlation is still missing. Thus, it is crucial to develop, refine and apply quantitative structure-function correlations using computer simulation approaches. In the past we have made a major progress in converting structures to functions in systems that involve proton transport (PTR) and charge transport. This was done by developing microscopic and coarse grained (CG) approaches including multiscale approaches that allow us to explore very long time processes. Our multiscale models has placed us in a position where we can advance in the following directions: (a) Simulating the time evolution of PTR in proteins using realistic yet practical methods, where we can quantify the action of key proton- conducting systems and advance the following projects: (i) exploiting our initial progress and continue to explore the gating mechanism of the redox-coupled cytochrome c oxidase (CcO), putting more effort on well- defined channels where the activation barriers for PTR are known, including in ba3-type and related systems. (ii) Exploiting our recent breakthrough in modeling the conversion of pH gradients across the FO-ATPase system to a vectorial rotation and gaining a better understanding of the relevant proton paths. (iii) Exploring voltage activated PTR in Hv1. (iv) Continuing in our study of the PTR in bacteriorhodopsin (bR). (v) Exploiting our progress in realistic modeling of membrane potential to interpret the observed relationship between these potentials and the paths of the PT steps in CcO. (b) Exploiting our recent advances in modeling voltage activated ion channels to advance the following projects: (i) quantifying the interplay between the electrode potential and the protein/membrane landscape in voltage activation processes, (ii) reproducing the gating current and the subsequent ion current and selectivity. (iii) Validating our simulation methods. (c) Modeling the action of transporters by our multiscale approaches. (iv) Considering the relations between our finding to various diseases.