New Theoretical Tools for Biocatalysis

描述（由申请人提供）：本研究的总体目标是为模拟生物催化的新型全量子力学力场建立基础，该力场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实现的复杂生物问题。这些新的计算工具的设计将大大扩展生物催化应用的范围，可以可靠地解决。这项工作的影响是从传统的混合量子力学/分子力学（QM/MM）模型转向统一的全量子力学方法，用于复杂环境中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、电荷依赖的多体交换、极化和色散效应的能力。Biocat-QM将构成QM/MM模型的基础，该模型包含一种新的QM/MM相互作用形式，其中非键项会根据电荷状态和杂化的变化自动调整。最终，Biocat-QM将被制成一种新的全量子力学力场，用于模拟生物催化，基于一种新的线性缩放量子方法，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。本提案中开发的模拟生物催化的新工具旨在克服特定驱动应用所带来的困难：核酶催化的分子机制研究。这些方法将应用于两种核酶系统，它们表现出大规模的构象变化和二价金属离子结合耦合催化，并且最近的结构数据已经通过合作者William Scott教授获得：全长锤头核酶和L1连接酶核酶/核开关。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现，优化并移植到几个高性能计算平台，并与分子模拟包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.