Simulation of Proton and Hydride Transfer in Enzymes

这项研究的广泛，长期目标是阐明基本原则和机制 蛋白质和RNA酶催化中的氢转移。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 关于结构重组和构象运动。这些计算将探讨 氢键，活性部位重组，氢隧道，活性部位水分子，静电， 以及蛋白质和RNA酶催化中的构象运动。这些理论研究将 与实验小组密切合作，协助解释实验结果。 数据，并提供实验测试的预测。蛋白酶项目将集中在大豆上 脂肪氧合酶和人类DNA聚合酶eta，RNA酶项目将集中在gImS和 扭转酶核酶大豆脂肪氧合酶作为研究氢隧道的原型， 酶，因为它表现出异常大的氢/氘动力学同位素效应。理论 的速率和动力学同位素效应的温度和压力依赖性的调查野生- 类型和突变酶将提供深入了解影响氢隧穿的运动。人类DNA 聚合酶eta使暴露于紫外线而受损的DNA能够复制， 了解其机制对皮肤癌的预防和治疗具有重要意义。 这种酶的模拟将提供深入了解这种生物医学上重要的酶的机制。 gImS和扭转酶核酶催化对于调节蛋白质表达至关重要的自切割反应。 合成和各种RNA加工反应。对这些核酶的理论研究将阐明它们的 这可能有助于核酶的发展，用作治疗剂切割 致病RNA。所有这些研究都与公共卫生有关，因为由此产生的基本 这些见解可以促进为各种疾病设计更有效的药物。 相关性（参见说明）： 这些研究与公共卫生有关，因为阐明酶的基本原理 催化将有助于设计更有效的酶，从而可能有助于开发 对包括皮肤癌在内的一系列疾病更有效的药物。对RNA催化的深入了解可能会 有助于开发用作切割致病RNA的治疗剂的RNA酶。

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.