Multi-level Quantum Methods for Phosphate Hydrolysis

该方案的目的是发展和应用新的集成多能级量子方法来研究金属离子催化的RNA中的磷酸水解反应。这些方法的发展重点包括(A)设计用于生物分子的新的线性标度电子结构方法，b)开发新的混合QM/MM势来模拟酶中的磷酸水解反应，以及c)实现用于量子力学几何优化和频率计算的新的线性标度光滑溶剂化势能。新的方法将被应用到CHARMM分子建模程序包中，并广泛使用。这些应用将集中在一个小的单磷酸水解模型体系和锤头状核酶自切割反应上。这些体系将用经典分子模拟、混合QM/MM方法和高水平密度泛函计算进行研究。特别令人感兴趣的是结构和活性之间的关系，以及金属离子在催化中的作用。这些系统提出了重要的生物学问题，并提出了特殊的理论挑战。拟议工作的目标是取得进展，以克服这些挑战。

The objective of this proposal is to develop and apply new integrated multi-level quantum methods to study metal-ion catalyzed phosphate hydrolysis reactions in RNA. The focus of the methods development include (a) the design of new linear-scaling electronic structure methods for biomolecules, b) the development of new hybrid QM/MM potentials to model phosphate hydrolysis reactions in enzymes, and c) the implementation of a new linear-scaling smooth solvation potential for quantum mechanical geometry optimization and frequency calculations. The new methods will be implemented into the CHARMM molecular modeling package and made widely available. The applications will focus on a small monophosphate hydrolysis model system, and on the hammerhead ribozyme self-cleavage reaction. These systems will be studied with classical molecular simulation, hybrid QM/MM methods, and high-level density-functional calculations. Of particular interest is the relationship between structure and activity, and the role of metal ions in catalysis. These systems pose important biological questions and present special theoretical challenges. The goal of the proposed work is to make advances to overcome these challenges.