Computational Studies of Histone Modifications

组蛋白修饰的计算研究

• 批准号: 8438864
• 负责人: Yingkai Zhang
• 金额: $ 29.32万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438864
• 关键词: Acetylation; Active Sites; Biochemical; Biological; Biomedical Research; Catalysis; Cell Death; Cell physiology; Chemistry; Computing Methodologies; Deacetylation; Development; Disease; Drug Targeting; EP300 gene; Electrostatics; Environment; Enzymatic Biochemistry; Enzymes; Epigenetic Process; Family; Free Energy; Gene Expression; Generations; Goals; Histone Acetylation; Histones; Knowledge; Longevity; Lysine; Malignant Neoplasms; Medical; Metabolic Pathway; Methodology; Methods; Modeling; Mutagenesis; Mutation; Nicotinamide adenine dinucleotide; Pathway interactions; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Proteins; Protocols documentation; Reaction; Regulation; Research; Role; Sampling; Simulate; Sirtuins; Staging; Testing; Therapeutic; Therapeutic Uses; Time; Transferase; Work; base; computer studies; design; enzyme activity; histone acetyltransferase; histone modification; human disease; improved; innovation; insight; interest; molecular dynamics; novel; public health relevance; research study; simulation; tool

DESCRIPTION (provided by applicant): Our long term goal is to develop and apply computational methods to provide novel mechanistic insights into catalysis and regulation of histone modifying enzymes, and to facilitate the rational design of enzyme sub-type specific modulators for probing epigenetic pathways and therapeutic use. Reversible histone acetylation has emerged as a vital regulator in a multitude of essential epigenetic processes. The enzymes responsible for this essential post-translational modification are histone acetyl transferases (HATs) and histone deacetylases (HDACs) that add and remove acetyl groups to and from target lysine residues, respectively. The aberrant activity of these enzymes has been implicated in numerous human diseases, notably cancer, and quite a few HATs and HDACs have been established as important drug targets. Our theoretical approaches will center on Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, a state-of-the-art computational approach to simulate enzyme reactions which allow for accurate modeling of the chemistry at the enzyme active site while properly including dynamics and effects of protein environment. The specific aims are: 1. Characterize the catalytic mechanism for HATs and rational redesign of tGcn5 for its improved efficiency. Aim 2: Elucidate inner workings of sirtuins, a novel family o class III histone deacetylases. Aim 3: Advance ab initio QM/MM methods. The successful completion of the proposed research will provide a detailed mechanistic understanding for HATs and sirtuins for the first time. This will stimulate further mechanistic studies of these important enzymes, and facilitate the development of novel mechanism-based modulators for probing acetylation dependent epigenetic pathways and for therapeutic use. Meanwhile, our methodology development efforts will significantly advance this computational tour de force to simulate enzyme reactions, and help establish it as an equal partner to experimental approaches in this important field of enzymology.

描述（由申请人提供）：我们的长期目标是开发和应用计算方法，为组蛋白修饰酶的催化和调节提供新颖的机制见解，并促进酶亚型特异性调节剂的合理设计，以探索表观遗传途径和治疗用途。可逆组蛋白乙酰化已成为多种重要表观遗传过程中的重要调节因子。负责这种重要翻译后修饰的酶是组蛋白乙酰转移酶 (HAT) 和组蛋白脱乙酰酶 (HDAC)，它们分别在目标赖氨酸残基上添加和去除乙酰基。这些酶的异常活性与许多人类疾病，尤其是癌症有关，并且相当多的 HAT 和 HDAC 已被确定为重要的药物靶点。我们的理论方法将以 Born-Oppenheimer 从头开始​​ QM/MM 分子动力学模拟为中心，这是一种模拟酶反应的最先进的计算方法，可以对酶活性位点的化学反应进行精确建模，同时正确地包括蛋白质环境的动力学和影响。具体目标是： 1. 表征 HAT 的催化机制并合理重新设计 tGcn5 以提高其效率。目标 2：阐明沉默调节蛋白（一个新的 III 类组蛋白脱乙酰酶家族）的内部运作机制。目标 3：推进从头开始的 QM/MM 方法。拟议研究的成功完成将首次为 HAT 和 Sirtuins 提供详细的机制理解。这将促进对这些重要的机制的进一步研究 酶，并促进基于机制的新型调节剂的开发，用于探测乙酰化依赖性表观遗传途径和治疗用途。同时，我们的方法开发工作将显着推进模拟酶反应的计算杰作，并帮助将其确立为酶学这一重要领域实验方法的平等伙伴。