Computational Studies of Histone Modifications

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许多重要表观遗传过程中的重要调节因子。负责这种必需的翻译后修饰的酶是组蛋白乙酰基转移酶（HAT）和组蛋白脱乙酰基酶（HDAC），其分别向靶赖氨酸残基添加乙酰基和从靶赖氨酸残基去除乙酰基。这些酶的异常活性与许多人类疾病，特别是癌症有关，并且相当多的HAT和HDAC已被确定为重要的药物靶标。我们的理论方法将集中在Born-Oppenheimer ab initio QM/MM分子动力学模拟上，这是一种模拟酶反应的最先进的计算方法，可以准确模拟酶活性位点的化学反应，同时适当地包括蛋白质环境的动力学和影响。具体目标是：1.表征HAT的催化机理，并合理地重新设计tGcn 5以提高其效率。目的2：阐明一个新的III类组蛋白去乙酰化酶家族sirtuins的内部工作机制。目的3：改进从头算QM/MM方法。这项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 酶，并促进开发用于探测乙酰化依赖性表观遗传途径和用于治疗用途的新的基于机制的调节剂。与此同时，我们的方法开发工作将显着推进这一计算巡回赛的力量，以模拟酶反应，并帮助建立它作为一个平等的合作伙伴，在酶学的这一重要领域的实验方法。

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.