Simulation of Proton and Hydride Transfer in Enzymes

这项研究的广泛、长期的目标是阐明基本原则和机制 蛋白质和核糖核酸酶催化的氢转移。这些目标将通过以下方式实现 广泛的理论和计算方法，包括经典的分子动力学模拟 以及提供原子级信息的混合量子力学/分子力学模拟 关于结构重排和构象运动。这些计算将探索 氢键，活性中心重组，氢隧道，活性中心水分子，静电学， 蛋白质和核糖核酸酶催化的构象运动。这些理论研究将是 与实验小组密切合作，协助解释实验 数据，并提供实验上可验证的预测。蛋白质酶项目将集中在大豆上 脂氧合酶和人类DNA聚合酶ETA，以及RNA酶项目将集中在GIMS和 扭曲核酶。大豆脂氧合酶作为研究氢隧道效应的原型 酶，因为它表现出异常大的氢/氚动力学同位素效应。理论上的 野生型同位素的速率和动力学同位素效应的温度和压力依赖关系的研究 类型和突变的酶将提供对影响氢隧道传输的运动的洞察。人类DNA 聚合酶ETA能够复制因暴露于紫外线而受损的DNA，以及 了解其作用机制对皮肤癌的预防和治疗具有重要意义。 对这种酶的模拟将提供对这种生物医学重要酶的机制的洞察。 GIM和TWISTER核酶催化自切反应，这是调节蛋白质所必需的 合成和各种RNA加工反应。对这些核酶的理论研究将解释它们的 核酶的作用机制，并可能有助于核酶的开发，用作切割的治疗剂 致病核糖核酸。所有这些研究都与公共健康相关，因为由此产生的基本 洞察力可以帮助设计出更有效的治疗各种疾病的药物。 相关性(请参阅说明)： 这些研究与公众健康相关，因为酶的基本原理的阐明 催化作用将促进更有效的酶的设计，从而潜在地帮助开发 为包括皮肤癌在内的多种疾病提供更有效的药物。对RNA催化的洞察可能 协助开发核糖核酸酶，用作裂解致病核糖核酸的治疗剂。

The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms of hydrogen transfer in both protein and RNA enzyme catalysis. These objectives will be accomplished with a wide range of theoretical and computational methods, including classical molecular dynamics simulations and mixed quantum mechanical/molecular mechanical simulations that provide atomic-level information about Structural rearrangements and conformational motions. These calculations will probe the roles of hydrogen bonding, active site reorganization, hydrogen tunneling, active site water molecules, electrostatics, and conformational motions in both protein and RNA enzyme catalysis. These theoretical studies will be performed in close collaboration with experimental groups, assisting in the interpretation of experimental data and providing experimentally testable predictions. The protein enzyme projects will focus on soybean lipoxygenase and human DNA polymerase eta, and the RNA enzyme projects will focus on the gImS and twister ribozymes. Soybean lipoxygenase serves as a prototype for investigating hydrogen tunneling in enzymes because it exhibits unusually large hydrogen/deuterium kinetic isotope effects. Theoretical investigations of the temperature and pressure dependence of the rates and kinetic isotope effects of wild- type and mutant enzymes will provide insight into the motions that impact hydrogen tunneling. Human DNA polymerase eta enables the replication of DNA that has been damaged by exposure to ultraviolet rays, and understanding its mechanism has significant implications for skin cancer prevention and treatment. Simulations of this enzyme will provide insight into the mechanism of this biomedically important enzyme. The gImS and twister ribozymes catalyze self-cleavage reactions that are essential for modulating protein synthesis and various RNA processing reactions. Theoretical studies of these ribozymes will illuminate their mechanisms and may assist in the development of ribozymes for use as therapeutic agents to cleave pathogenic RNAs. All of these studies are relevant to public health because the resulting fundamental insights could facilitate the design of more effective drugs for a wide range of diseases. RELEVANCE (See instructions): These studies are relevant to public health because the elucidation of fundamental principles of enzyme catalysis will facilitate the design of more efficient enzymes, thereby potentially assisting in the development of more effective drugs for a broad range of diseases, including skin cancer. Insights into RNA catalysis may assist in the development of RNA enzymes for use as therapeutic agents to cleave pathogenic RNAs.