Multiscale Simulations of Biological Systems and Processes

生物系统和过程的多尺度模拟

• 批准号: 10406537
• 负责人: ARIEH WARSHEL
• 金额: --
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406537
• 关键词: ATP phosphohydrolase; Active Sites; Biochemical Reaction; Biological Process; COVID-19 pandemic; Catalysis; Cells; Charge; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Computer Assisted; Computer Simulation; Computing Methodologies; Coupled; Development; Directed Molecular Evolution; Disease; Drug Design; Drug resistance; Electrodes; Electrolytes; Electron Transport; Entropy; Enzymes; Experimental Designs; Free Energy; G-Protein-Coupled Receptors; Grain; Ion Channel Gating; Ions; Life; Medical; Membrane Proteins; Methods; Microscopic; Modeling; Molecular; Pharmaceutical Preparations; Process; Proteins; Protons; Structure; Surface; System; biological systems; complex biological systems; cytochrome c oxidase; design; experimental group; experimental study; fighting; improved; multi-scale modeling; screening; simulation; trend; voltage

Project Summary In order to advance the understanding of life processes at the molecular level, we developed multiscale computer simulations that can treat complex biological systems. We intend to apply such strategies to systems which are to important medical problems. Our proposed projects are listed below. A.1 Enzymatic Processes: By exploiting our advances in multiscale modeling, we intend to progress in the following directions: (a) Quantifying computer-aided enzyme design by: (i) reproducing the observed trend in experiments of directed evolution using automatic configuration generator coupled with EVB simulations; (ii) reproducing the catalytic activity of experimentally designed enzymes; (iii) improving the action of promiscuous enzymes; (iv) destroying and rebuilding active sites. Our studies will be done in collaboration with key experimental groups. (b) Continuing to advance the quantitative computational methods, including: (i) using our PD QM(ai)/MM method in for evaluating the ab initio free energy surfaces of enzymatic reactions; (ii) Advancing a maximum entropy approach for fast screening (iii) Quantifying the relationship between folding and catalysis; (c) Conducting studies on important classes of enzymes; (d) Exploring the relations of our findings to medical problems such as the Covid-19 pandemic, drug resistance and other topics like CRISPR. A.2 Multiscale Modeling of the energetics and functions of complex biological systems: Basic functions of living cells are underpinned by proteins that guide the transport of electrons, protons, and ions. Thus, it is crucial to quantitatively explore and exploit the structure-function correlations using computer simulation approaches. We have made a major progress in developing microscopic and coarse grained (CG) approaches for such systems, and we will advance them in the following directions: (a) Simulating the proton transfer (PTR) gating mechanism of cytochrome c oxidase (CcO) and extending our recent studies of FO-ATPase. (b) Exploiting our advances in modeling voltage-gated ion channels for the following purposes: (i) to quantify the interplay between the electrode potential and the protein/membrane energy landscape, (ii) to reproduce the gating voltage and the subsequent ion current and its selectivity using both CG and explicit MC electrolyte models, (iii) to simulating the action of GPCRs and transporters by CG approach, (iv) to explore the relations between our finding and various diseases.

项目摘要 为了促进分子层面生活过程的理解，我们开发了多尺度计算机 可以处理复杂生物系统的模拟。我们打算将这些策略应用于系统 解决重要的医疗问题。我们提出的项目在下面列出。 A.1酶促过程：通过利用我们在多尺度建模方面的进步，我们打算进步 以下说明：（a）量化计算机辅助酶设计作者：（i）重现观察到的趋势 使用自动构型生成器与EVB仿真相结合的定向进化实验； （ii） 重现实验设计的酶的催化活性； （iii）改善混杂的作用 酶； （iv）破坏和重建主动地点。我们的研究将与Key合作完成 实验组。 （b）继续推进定量计算方法，包括：（i）使用我们的 PD QM（AI）/MM方法，用于评估酶促反应的初始自由能表面； （ii）前进 快速筛选（III）的最大熵方法，量化了折叠与催化之间的关系； （c）对重要类酶进行研究； （d）探索我们发现与医疗的关系 COVID-19大流行，耐药性和其他主题等问题等问题。 A.2复杂生物系统的能量和功能的多尺度建模：基本功能 活细胞的基础是指导电子，质子和离子传输的蛋白质。因此，是 对于使用计算机仿真来定量探索和利用结构 - 功能相关性至关重要 方法。我们在开发微观和粗粒（CG）方法方面取得了重大进展 对于此类系统，我们将向以下方向推进它们：（a）模拟质子转移（PTR） 细胞色素C氧化酶（CCO）的门控机制，并扩展了我们最近对FO-ATPase的研究。 （b）剥削 我们为以下目的对电压门控离子通道进行建模的进步：（i）量化相互作用 在电极电位和蛋白质/膜能量景观之间，（ii）重现门控电压 以及随后的离子电流及其选择性使用CG和显式MC电解质模型，（III） 通过CG方法（IV）模拟GPCR和转运蛋白的作用，以探索我们的关系 发现和各种疾病。