Biomolecular Interactions and Enzymatic Processes

描述(由申请人提供)：一个多方面的研究项目旨在对水溶液中的酶过程进行计算研究。理论方法的中心是使用量子力学和分子力学(QM/MM)相结合的方法对酶反应的分子动力学自由能进行模拟。为了获得更高的精度和能力，我们建议进一步改进混合分子轨道和价键(MOVB)理论，以便生物化学家可以方便地校准、验证和使用它作为帮助解释实验结果的计算工具。MOVB理论将通过从头算和半经验分子轨道和密度泛函理论来实现和分布。此外，我们计划在QM/MM组合计算中加入显式极化效应，这可以显著提高描述酶和底物相互作用的一致性的准确性。一个主要的目的是提供对酶反应的基本原理和机制的更深入的理解。在此期间，我们旨在阐明组蛋白赖氨酸去甲基酶的催化起源，它通过不同的机制和使用不同的酶辅助因子催化相同的化学转化。另一方面，对L-多巴脱羧酶的研究，可以提供对不同酶利用磷酸吡哆醛辅因子进行化学选择性的洞察。组蛋白赖氨酸去甲基酶是新近发现的两类能动态控制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，其结果将对蛋白质工程和抑制剂设计具有普遍意义。与公共健康相关：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蛋白质靶标的药物，这些蛋白质靶标是导致癌症生长和其他疾病的原因。这项建议中描述的研究旨在从根本上了解催化化学反应的酶和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设计用于生物医学和工业应用的特殊蛋白质。

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.