Biomolecular Interactions and Enzymatic Processes

描述（由申请人提供）：一个多方面的研究项目是针对在水溶液中的酶过程的计算研究。理论方法集中在分子动力学自由能模拟酶促反应使用结合量子力学和分子力学（QM/MM方法）。为了实现更高的准确性和能力，我们建议进一步改进混合分子轨道和价键（MOVB）理论，使其可以方便地校准，验证和使用的生物化学家作为计算工具，以帮助解释实验结果。MOVB理论将实施和分发的能力，使用从头算和半经验分子轨道和密度泛函理论。此外，我们计划将显式极化效应结合到组合QM/MM计算中，这可以显着提高描述酶和底物相互作用的准确性。一个主要的推动力是提供一个更深入的了解的基本原则和机制的酶促反应。在此期间，我们的目标是阐明组蛋白赖氨酸脱甲基酶的催化起源，这些酶通过不同的机制和使用不同的酶辅因子催化相同的化学转化。另一方面，对L-多巴脱羧酶（一种与治疗帕金森病相关的酶）的研究可以提供对采用磷酸吡哆醛辅因子的不同酶的化学选择性的了解。组蛋白赖氨酸去甲基化酶是近年来发现的两类动态调控染色质甲基化状态的酶，与基因激活和基因沉默有关，是抗癌药物的潜在靶点。此外，我们试图解决蛋白质动力学和酶重组能量对催化的影响。MOVB方法为研究这些问题提供了一个重要的研究工具，其结果对蛋白质工程和抑制剂设计具有重要意义。公共卫生相关性：蛋白质是活细胞中的主力，执行从新陈代谢到细胞生长的所有基本任务。一个重要的目标是开发针对负责癌症生长和其他疾病的蛋白质靶点的药物。该提案中描述的研究旨在从根本上了解酶和催化化学反应的蛋白质的机制和功能，从这些研究中获得的知识可以帮助设计抑制剂和工程专用蛋白质用于生物医学和工业应用。

DESCRIPTION (provided by applicant): A multi-faceted research project is directed aimed at computational studies of enzymatic processes in aqueous solution. The theoretical approach centers on molecular dynamics free energy simulations of enzymatic reactions using combined quantum mechanical and molecular mechanical (QM/MM methods. To achieve greater accuracy and capability, we propose to further improve the mixed molecular orbital and valence bond (MOVB) theory such that it can be conveniently calibrated, validated and used by biochemists as a computational tool to help interpret experiment findings. The MOVB theory will be implemented and distributed with the capability of using ab initio and semiempirical molecular orbital and density functional theory. In addition, we plan to incorporate explicit polarization effects into combined QM/MM calculations, which can significantly increase the accuracy to describe enzyme and substrate interactions consistently. A major thrust is to provide a deeper understanding of the underlying principles and mechanisms of enzymatic reactions. During this grant period, we aim to elucidate the origin of catalysis in histone lysine demethylases, which catalyze the same chemical transformation by different mechanisms and using different enzyme cofactors. On the other hand, studies of the L-dopa decarboxylase, an enzyme related to the treatment of Parkinson's disease, can provide insight into chemical selectivity by different enzymes employing the pyridoxal phosphate cofactor. Histone lysine demethylases are two classes of enzymes recently discovered to dynamically control the methylation states of chromatin, which are related to gene activation and gene silencing and these enzymes are potential targets for anticancer drugs. In addition, we seek to address the effects of protein dynamics and enzyme reorganization energies on catalysis. The MOVB method provides an important research tool to study these questions, and the results will be of general importance to protein engineering and inhibitor design. PUBLIC HEALTH RELEVANCE: Proteins are workhorses in the living cell, performing all the fundamental tasks from metabolism to cell growth. An important goal is to develop pharmaceutical drugs against protein targets that are responsible for cancer growth and other diseases. The research described in this proposal aims at the fundamental understanding of the mechanism and function of enzymes, proteins that catalyze chemical reactions, and the knowledge gained from these studies can help design inhibitors and engineer specialized proteins for biomedical and industrial applications.