New Theoretical Tools for Biocatalysis

描述（由申请人提供）：本研究的广泛目标是为一种新型的全量子力学力场建立基础，用于模拟生物催化，可以与其他多尺度建模工具无缝集成，并应用于其他方法无法访问的复杂生物问题。这些新的计算工具的设计将大大扩展可以可靠解决的生物催化应用的范围。这项工作的影响是创造一个范式转变，从传统的混合量子力学/分子力学（QM/MM）模型向一个统一的完全量子力学的方法，在复杂的环境中的反应过程的分子模拟。核心方法将基于一种新的生物催化量子力学模型（Biocat-QM），该模型结合了现有半经验模型的优点，并扩展了其准确模拟反应势垒以及电荷依赖性多体交换，极化和色散效应的能力。Biocat-QM将形成QM/MM模型的基础，该模型包含一种新形式的QM/MM相互作用，其中非键合项自动调整以响应电荷状态和杂交的变化。最终，Biocat-QM将成为一种新型的全量子力学力场，用于模拟生物催化，基于一种新的线性尺度量子方法，该方法利用密度重叠排斥模型来规避对大型局部基础投影的需要，并利用最近开发的自适应快速多极算法来有效计算广义电荷分布的静电相互作用。在这项建议中开发的生物催化模拟的新工具，旨在克服特定的驱动应用程序所提出的困难：核酶催化的分子机制的研究。该方法将被应用到两个核酶系统，表现出大规模的构象变化和二价金属离子结合与催化偶联，并为最近的结构数据已成为通过合作者威廉·斯科特教授：全长锤头状核酶和L1连接酶核酶/核糖开关。这些系统提出了独特的挑战，目前还没有足够可靠的生物催化模拟模型。本提案中开发的计算工具将作为公开可用的模块化软件实施，优化并移植到几个高性能计算平台，并与分子模拟软件包AMBER和CHARMM集成。

DESCRIPTION (provided by applicant): The broad objective of this research is to establish the foundation for a novel fully quantum mechanical forcefield for simulations of biocatalysis that can be seamlessly integrated with other multi-scale modeling tools and applied to complex biological problems not accessible by other methods. The design of these new computational tools will greatly extend the scope of biocatalysis applications that can be reliably addressed. The impact of this work with be to create a paradigm shift away from conventional mixed quantum mechanical/molecular mechanical (QM/MM) models toward a united fully quantum mechanical approach for molecular simulations of reactive processes in complex environments. The core methods will be based on a new quantum mechanical model for biocatalysis (Biocat-QM) that combines the advantages of existing semiempirical models and extends their capabilities to accurately model reaction barriers, and charge-dependent many-body exchange, polarization and dispersion effects. The Biocat-QM will form the base of a QM/MM model that contains a new form of the QM/MM interaction where non-bonded terms automatically adjust in response to changes in charge state and hybridization. Ultimately, the Biocat-QM will be made into a novel fully quantum mechanical forcefield for simulations of biocatalysis, based on a new linear-scaling quantum method that utilizes a density-overlap repulsion model to circumvent the need for large local basis projections, and that takes advantage of a recently developed adaptive fast-multipole algorithm for efficient calculation of electrostatic interactions for generalized charge distributions. The new tools for simulations of biocatalysis developed in this proposal are designed to surmount the difficulties presented by specific driving applications: the study of the molecular mechanisms of ribozyme catalysis. The methods will be applied to two ribozyme systems that exhibit large-scale conformational changes and divalent metal ion binding coupled with catalysis, and for which very recent structural data has become available through collaborator Prof. William Scott: the full length hammerhead ribozyme and the L1 ligase ribozyme/riboswitch. These systems present unique challenges for which there currently exists no sufficiently reliable biocatalysis simulation model. The computational tools developed in this proposal will be implemented as publicly available modular software, optimized and ported to several high-performance computing platforms, and integrated with the molecular simulation packages AMBER and CHARMM.