Multi-scale Quantum Models for Ribozyme Catalysis

描述（由申请人提供）：这是一个应用驱动的提案，重点是通过使用最先进的理论方法对RNA催化的分子机制提供新的见解。为了实现这一目标，采取了多方面的方法，结合了量子化学，分子模拟和统计力学方法，其中许多方法一直是NIH最初资助期间的发展重点。这些方法被统称为RNA催化的“多尺度”模型：集成方法，当共同使用时，能够同时跨越所需的广泛的空间和时间域，以提供对核酶分子机制的更深入的理解。这些方法的持续发展和扩展在这一更新建议中起着重要作用，包括磷酰基转移反应的新半经验量子模型的设计，QM/MM模拟的线性标度静电和电子结构方法的扩展和增强，以及溶剂化和广义大分子溶剂边界势和响应的处理的改进模型。尽管如此，主要的优先事项是应用最近开发的方法已经提供的问题，发生在溶液中和核酶中的磷酰基转移反应。为了这个目的，我们建议校准和验证新的多尺度模型对重要的非酶反应，已被实验研究，然后将它们应用到一组集中的三个原型核酶系统：锤头，发夹和丁型肝炎病毒核酶。这些核酶已经通过实验进行了广泛的研究（包括不同催化阶段的结构信息），并在其交替催化机制方面提供了高度互补的功能。这些系统的研究可以更深入地了解哪些功能是保守的，哪些功能可能会被利用在新的核酶的工程，可能有相当大的希望在生物医学研究，治疗的设计，或新的生物/纳米技术的发展。

DESCRIPTION (provided by applicant): This is an application-driven proposal that focuses on providing new insight into the molecular mechanisms of RNA catalysis through use of state-of-the-art theoretical methods. To achieve this goal, a multi-faceted approach is taken that combines quantum chemistry, molecular simulation and statistical mechanical methods, many of which have been the development focus of the initial NIH funding period. These methods are collectively referred to as "multi-scale" models for RNA catalysis: integrated methods that, when used collectively, are able to simultaneously span the broad range of spatial and temporal domains required to provide a deeper understanding of the molecular mechanisms of ribozymes. Continued development and extension of these methods plays a strong role in this renewal proposal, including the design of new semiempirical quantum models for phosphoryl transfer reactions, extension and enhancement of linear- scaling electrostatic and electronic structure methods for QM/MM simulations, and improved models for treatment of solvation and generalized macromolecular solvent boundary potential and response. Nonetheless, the main priority is to apply the recently developed methods already available to problems of phosphoryl transfer reactions that occur in solution and in ribozymes. For this purpose, we propose to calibrate and validate the new multi-scale models against important non-enzymatic reactions that have been studied experimentally, and then apply them to a focused set of three prototype ribozyme systems: the hammerhead, hairpin and hepatitis delta virus ribozymes. These ribozymes have been extensively studied by experiment (including structural information at different stages of catalysis), and offer highly complementary features in terms of their alternate catalytic mechanisms. Study of these systems in concert allows deeper insight into which features are conserved and which features might be exploited in the engineering of new ribozymes that may have considerable promise in biomedical research, the design of therapeutics, or development of new bio/nanotechnology.