Multiscale Simulations of Biological Systems and Processes

项目摘要 为了在分子水平上推进对生命过程的理解，我们发展了多尺度计算机 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以下系统： 重要的医疗问题。我们建议的项目如下。 A.1酶促过程：通过利用我们在多尺度建模方面的进展，我们打算在酶促过程方面取得进展。 （a）通过以下方式量化计算机辅助酶设计：（i）再现观察到的以下趋势： 使用自动配置生成器与EVB模拟相结合的定向进化实验;（ii） 复制实验设计的酶的催化活性;（iii）改善混杂酶的作用。 酶;（iv）破坏和重建活性位点。我们的研究将与主要的 实验组。(b)继续推进定量计算方法，包括：（i）使用我们的 用PD QM（ai）/MM方法计算酶促反应的从头算自由能表面;（ii）推进 最大熵方法快速筛选（iii）量化折叠和催化之间的关系; (c)对重要的酶类别进行研究;（d）探讨我们的研究结果与医学的关系 新冠肺炎大流行、耐药性和CRISPR等其他问题。 A.2复杂生物系统的能量学和功能的多尺度建模：基本功能 活细胞的生命是由蛋白质支撑的，蛋白质引导电子、质子和离子的运输。照经上所 利用计算机模拟定量探索和利用结构-功能相关性至关重要 接近。我们在发展微观和粗粒度（CG）方法方面取得了重大进展 对于这样的系统，我们将在以下方向推进：（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)利用 我们在模拟电压门控离子通道方面的进展，目的如下：（i）量化相互作用 在电极电势和蛋白质/膜能量景观之间，（ii）再现门控电压 和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方法模拟GPCRs和转运蛋白的作用，（iv）探索我们的GPCRs和转运蛋白之间的关系。 发现和各种疾病。

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.