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，为组蛋白编码提供理论基础。形成核小体核心的组蛋白经历了各种翻译后转换。这些组蛋白修饰组成了组蛋白密码，它延伸了遗传密码中的信息，并正在成为调节基因表达的一种基本机制。适当的组蛋白修饰失败会导致基因调控异常，并与人类疾病有关，尤其是癌症。尽管目前在实验研究方面取得了一系列重大进展，但对于组蛋白密码是如何编写的，即酶如何产生或移除这些修饰，在理论上还知之甚少。在这个方案中，我们主要关注两个重要的组蛋白修饰酶家族：I类和II类组蛋白脱乙酰酶(HDAC)和组蛋白赖氨酸甲基转移酶(HKMTs)。前者是最有希望开发抗肿瘤药物的靶点之一，而组蛋白赖氨酸甲基化已在与年龄相关的神经退行性疾病和癌症的研究中得到解决。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)相结合的方法上，这些方法允许对酶活性部位的化学进行准确的建模，同时适当地包括蛋白质环境的影响。在目标1中，我们将表征I类和II类组蛋白脱乙酰基酶的催化机理。在目标2中，我们将研究HKMT，以提供详细的见解，了解组蛋白赖氨酸甲基化的产物特异性是如何实现的。在目标3中，将开发新的从头计算QM/MM方法，以进一步提高其精度、效率和能力。这些拟议的研究不仅将对这一新的和重要的分子生物学领域做出根本性的贡献，而且应该有助于设计新的基于机制的药物来治疗由组蛋白异常修饰引起的疾病。

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.