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最先进的计算方法来提供组蛋白密码的理论基础。形成核小体核心的组蛋白受到各种翻译后转化的影响。这些组蛋白修饰构成了组蛋白密码，扩展了遗传密码中的信息，并逐渐成为调控基因表达的重要机制。适当组蛋白修饰的失败可导致基因调控异常，并与人类疾病，特别是癌症有关。尽管目前在实验研究中取得了一系列重大进展，但关于组蛋白密码是如何编写的，即酶是如何产生或去除这些修饰的，理论上的理解很少。在本提案中，我们主要关注两个重要的组蛋白修饰酶家族：I类和II类组蛋白去乙酰化酶（hdac）和组蛋白赖氨酸甲基转移酶（hkmt）。前者是开发抗肿瘤药物最有希望的目标之一，而组蛋白赖氨酸甲基化已经在与年龄相关的神经退行性疾病以及癌症的研究中得到了解决。我们的理论方法将集中在从头算量子力学和分子力学（QM/MM）方法的结合上，这种方法可以准确地模拟酶活性位点的化学反应。包括蛋白质环境的影响。在目标1中，我们将描述I类和II类组蛋白去乙酰化酶的催化机制。在目标2中，我们将研究hkmt，以提供关于如何实现组蛋白赖氨酸甲基化产物特异性的详细见解。在目标3中，将开发新的从头算QM/MM方法，以进一步提高其精度，效率和能力。这些建议的研究不仅将为分子生物学这一新的重要领域做出根本性的贡献，而且还将促进设计基于机制的新型药物，用于治疗由异常组蛋白修饰引起的疾病。

DESCRIPTION (provided by applicant): Our long term goal is to develop and apply state-of-the-art computational methods to provide theoretical underpinnings of the histone code. Histone proteins that form the nucleosome core are subject to a variety of post-translational transformations. These histone modifications make up the histone code which extends the information in the genetic code and is emerging as an essential mechanism to regulate gene expression. Failure of appropriate histone modifications can lead to aberrant gene regulation and is implicated in human diseases, notably cancer. In spite of a current flurry of significant advances in experimental studies, there has been little theoretical understanding regarding how the histone code is written, i.e., how enzymes generate or remove these modifications. In this proposal, we mainly focus on two such important histone-modifying enzyme families: Class I and II histone deacetylases (HDACs), and histone lysine methyltransferases (HKMTs). The former are among the most promising targets for the development of anti-tumor drugs, while histone lysine methylation has been addressed in studies of age-related neurodegenerative disorders as well as cancer. Our theoretical approaches will center on the combined ab initio quantum mechanical and molecular mechanical (QM/MM) methods, which allow for accurate modeling of the chemistry at the enzyme active site while properly .including the effects of protein environment. In aim 1, we will characterize the catalytic mechanism for class I and II histone deacetylases. In aim 2, we will investigate HKMTs to provide detailed insights into how the product specificity of histone lysine methylation is achieved. In aim 3, new ab initio QM/MM methods will be developed to further improve its accuracy, efficiency and capability. These proposed studies will not only make fundamental contributions to this new and important area of molecular biology, but also should facilitate the design of novel mechanism-based drugs for diseases stemming from aberrant histone modifications.