Multiscale Simulations of Biological Systems and Processes

生物系统和过程的多尺度模拟

• 批准号: 9275185
• 负责人: ARIEH WARSHEL
• 金额: $ 22.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275185
• 关键词: ATP phosphohydrolase; Amino Acid Sequence; Bacteriorhodopsins; Biochemical; Biochemical Process; Biochemical Reaction; Bioenergetics; Biological; Biological Process; Catalysis; Cells; Cereals; Charge; Collaborations; Computer Assisted; Computer Simulation; Computing Methodologies; Coupled; Development; Directed Molecular Evolution; Disease; Drug Transport; Drug resistance; Electrodes; Electron Transport; Enzymes; Evolution; Free Energy; Health; Human; Ion Channel; Ions; Lead; Life; Medical; Membrane; Membrane Potentials; Membrane Proteins; Methods; Microscopic; Modeling; Molecular; Mutation; Organism; Oxidases; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Proteins; Proton Pump; Protons; Research; Role; Rotation; Signal Transduction; Structure; Surface; System; Therapeutic Intervention; Time; biological systems; complex biological systems; cytochrome c oxidase; design; drug development; drug discovery; experimental study; fighting; frontier; improved; membrane model; multi-scale modeling; neurotransmission; pH gradient; pathogen; simulation; targeted treatment; tool; vector; voltage; ATP phosphohydrolase; Amino Acid Sequence; Bacteriorhodopsins; Biochemical; Biochemical Process; Biochemical Reaction; Bioenergetics; Biological; Biological Process; Catalysis; Cells; Cereals; Charge; Collaborations; Computer Assisted; Computer Simulation; Computing Methodologies; Coupled; Development; Directed Molecular Evolution; Disease; Drug Transport; Drug resistance; Electrodes; Electron Transport; Enzymes; Evolution; Free Energy; Health; Human; Ion Channel; Ions; Lead; Life; Medical; Membrane; Membrane Potentials; Membrane Proteins; Methods; Microscopic; Modeling; Molecular; Mutation; Organism; Oxidases; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Proteins; Proton Pump; Protons; Research; Role; Rotation; Signal Transduction; Structure; Surface; System; Therapeutic Intervention; Time; biological systems; complex biological systems; cytochrome c oxidase; design; drug development; drug discovery; experimental study; fighting; frontier; improved; membrane model; multi-scale modeling; neurotransmission; pH gradient; pathogen; simulation; targeted treatment; tool; vector; voltage

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.

项目摘要 了解过去几十年来了解人类健康分子基础的进步已经是 巨大的。但是，在有关结构和结构的信息的转换方面，我们远远落后 蛋白质的序列成相应的功能。在这方面的进展可以大大提高 多尺度计算机模拟可以以增加的复杂性来处理不同系统。在这个 我们准备将这种方法应用于与重要医学有关的系统的系统 问题，包括研究酶设计，耐药性和质子和离子的运输机制， 从而阐明了生活系统中催化控制，生物能和能量转导的基础。我们的 拟议的协同方向如下列出。 A.1酶控制生化过程：许多疾病可以通过开发药物来控制 这阻断了酶在关键的生物学途径中的作用。结构和 生化研究尚未导致对酶促反应能量学的定量理解。 进一步的定量进度需要可靠的工具来实现酶的结构功能相关性。我们的 朝这个方向的进步导致开发有效的多尺度方法来模拟酶 催化。在此阶段，要利用我们的进步并同时进步很重要 方向：（a）量化计算机辅助酶设计作者：（i）重现观察到的催化作用 EVB和其他多尺度方法的主要设计师酶。 （ii）使用我们的多尺度方法 酶设计项目，包括更改混杂酶的作用，改善可用设计师 酶并帮助设计新酶。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 评估酶促反应的初始自由能表面； （ii）使用PD方法自动 精炼EVB表面，用于探索长距离突变效应和催化景观； （iii） 量化折叠与稳定性之间的关系。 （c）探索定向进化的催化作用 并确定其与自然​​进化的关系。 （d）进行重要类酶促的研究 反应。 （e）将探讨我们发现与医疗问题（包括耐药性）的关系。 A.2复杂生物系统的能量和功能的多尺度建模：蛋白质的蛋白质 指导电子，质子和离子的运输基于活细胞的基本功能。例如，质子 泵调节电化学梯度驱动分子跨膜的运输。 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。破坏的突变 这种系统的作用与许多毁灭性疾病有关。因此，这些蛋白质存在 治疗干预和在药物发现工作中起着核心作用的主要目标。尽管最近 质子泵，离子通道和相关系统研究中的结构和生化进展，有 许多情况下仍然缺少定量结构 - 功能相关性。因此，发展至关重要， 使用计算机模拟方法来完善并应用定量结构 - 功能相关性。在过去 我们在将结构转换为涉及质子传输的系统的功能方面取得了重大进展 （PTR）和充电运输。这是通过开发微观和粗粒（CG）方法来完成的 包括使我们能够探索很长时间流程的多尺度方法。我们的多尺度模型有 将我们置于可以朝以下方向前进的位置：（a）模拟时间演变 使用现实但实用方法中的蛋白质中的PTR，我们可以量化关键质子的作用 进行系统并推进以下项目：（i）利用我们的最初进步并继续 探索氧化还原耦合的细胞色素C氧化酶（CCO）的门控机制，为良好的努力付出了更多的努力 已知的PTR激活壁垒的定义通道，包括在BA3型和相关系统中。 （ii）利用我们最近在建模pH梯度在FO-ATPase上的转化方面的突破 系统到矢量旋转并更好地了解相关的质子路径。 （iii）探索 电压激活HV1中的PTR。 （iv）继续我们研究细菌紫红素（BR）的PTR。 （v）利用 我们在膜的现实建模中的进展，解释这些观察到的关系 电势和PT步骤中CCO的路径。 （b）利用我们最近在建模电压上的进步 激活的离子通道以推进以下项目：（i）量化电极之间的相互作用 电势和蛋白质/膜景观在电压激活过程中，（ii）重现门控 电流和后续离子电流和选择性。 （iii）验证我们的仿真方法。 （c）建模 我们的多尺度方法的转运蛋白作用。 （iv）考虑我们的发现与 各种疾病。