Computer Simulation of Enzymatic Reactions

酶反应的计算机模拟

• 批准号: 8627932
• 负责人: ARIEH WARSHEL
• 金额: $ 32.42万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-01-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627932
• 关键词: Active Sites; Bacteria; Binding; Biochemical; Biochemical Reaction; Biological; Catalysis; Cereals; Chemicals; Collaborations; Complement; Computer Assisted; Computer Simulation; Computers; Computing Methodologies; Consensus; Development; Disease; Drug resistance; Enzymes; Evaluation; Evolution; Free Energy; Genetic Engineering; Lead; Life; Methods; Modeling; Mutation; Nature; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Process; Proteins; Reaction; Relative (related person); Research; Ribosomes; Role; Simulate; Staging; Structure; Surface; Testing; Validation; Virus; base; biological systems; design; directed evolution; drug development; enzyme structure; enzyme substrate complex; fighting; frontier; improved; metalloenzyme; pathogen; public health relevance; research study; screening; simulation; thermostability; tool

Project Summary Since enzymes are involved in most life processes, it is crucial to gain a detailed understanding of their action. The importance of such an understanding is highlighted by the fact that many diseases can be controlled by developing drugs that block the action of enzymes in crucial biological pathways of pathogens that cause these diseases. Quantifying the analysis of enzyme catalysis can be greatly advanced by computer simulation approaches that correlate enzyme structures with their activity. Here the progress should involve both advances in quantifying the fundamental basis of enzyme catalysis and in developing practical predictive power in studies of diverse classes of enzymes. Thus we propose to continue in advancing the frontiers of this field, while shifting a significant part of our focus to the the emerging field of enzyme design. The advances on this front should provide a deeper understanding of catalysis, help in controlling what a given enzyme is doing as well as the use of specialized enzymes. We note, however, that the progress in enzyme design has not yet led to designer enzymes that rival native enzymes. Thus, it is clear that the potential of this field can be greatly enhanced by computational approaches that evaluate the activation barriers of the reactions that are being catalyzed. In order to progress in both quantifying enzyme design and in enhancing the general understanding of enzyme catalysis, we propose parallel advances in the following directions: (i) We will validate the reliability of our EVB-based computer-aided enzyme design by reproducing the observed catalytic effects of key designer enzymes. (ii) We will continue to develop more quantitative design concepts as well as fast screening methods. After exploring the predictive power of these approaches, we will use them in collaboration with research groups that are involved in actual enzyme design experiments. (iii) We will continue to advance quantitative computational methods including the paradynamics QM(ai)/MM-FEP approach that should help us to obtain activation free energies of enzymatic reactions by ab initio methods. (iv) We will quantify the relationship between folding and stability and explore the relationship between thermostability and catalysis. (v) We will explore the catalytic effect of directed evolution, trying to elucidate its relationship to natural evolution. (vi) We will conduct studies of several important classes of enzymatic reactions. (vii) We will continue with the systematic examination of different nonelectrostatic catalytic proposals.

项目摘要 由于酶参与了大多数生命过程，因此对他们的详细了解至关重要 行动。这种理解的重要性是由许多疾病可能是 通过开发的药物控制，该药物阻止酶在病原体的关键生物学途径中的作用 这会导致这些疾病。量化酶催化的分析可以通过计算机大大提出 模拟方法将酶结构与其活性相关联。在这里，进度应涉及 量化酶催化的基本基础和发展实践预测的基本基础方面的两种进步 各种酶类别的研究。因此，我们建议继续前进的前沿 田地，同时将我们重点的很大一部分转移到了新兴酶设计领域。进步 这一方面应该更深入地了解催化，帮助控制给定酶正在做的事情 以及使用专用酶。但是，我们注意到酶设计的进度尚未 导致了与天然酶相抗衡的设计酶。因此，很明显，该领域的潜力可能很大 通过评估正在反应的激活屏障的计算方法增强 催化。为了在量化酶设计和增强一般理解方面取得进展 在酶催化中，我们提出了以下方向的并行进步： （i）我们将通过重现基于EVB的计算机辅助酶设计的可靠性 观察到关键设计酶的催化作用。 （ii）我们将继续开发更定量的设计 概念以及快速筛选方法。探索了这些方法的预测能力后，我们将 与参与实际酶设计实验的研究小组合作使用它们。 （iii）我们 将继续推进包括Paradyanics QM（AI）/MM-FEP在内的定量计算方法 应有助于我们通过Ab始于方法获得酶促反应的激活能量的方法。 （iv） 我们将量化折叠与稳定性之间的关系，并探索 热稳定性和催化。 （v）我们将探索定向进化的催化作用，试图阐明其 与自然进化的关系。 （vi）我们将对几类酶促进行研究 反应。 （vii）我们将继续对不同非电压催化的系统检查 建议。