Design and application of robust and efficient QM/MM free energy simulation methods for biomolecular systems

项目摘要/摘要 为了准确地计算复杂生物分子体系的自由能，有两个关键的先决条件：准确的 分子间和分子内相互作用的描述，以及对所有相关构象程度的充分采样 自由。包括构象动力学可能与复杂的电子过程或 需要量子力学(QM)方法的化学反应，这项任务变得极其艰巨- 英。目前，只要生物分子系统的精确计算是必不可少的，选择的工具就是混合工具 然而，量子力学/分子力学(QM/MM)计算，这些技术的应用 自由能模拟(FES)远不常见。在这里，我们的目标是开发一套健壮、有效、准确的fi 将使QM/MM FES的应用近乎常规化的新技术。这些方法随后将被应用于- 致力于研究对当前技术构成极端挑战的两类生物分子应用。也就是说， (1)作为配体结合和反应的函数的绝对pKa的准确计算(例如，考虑反式 相互作用)，以及(2)作为互变异构化函数的结合自由能差。Sciencefic的结果将会是 与旨在改善获得这些先进技术的机会的活动密切相关。

Project Summary / Abstract To accurately compute free energies of complex biomolecular systems there are two key prerequisites: the accurate description of inter- and intramolecular interactions, and adequate sampling of all relevant conformational degrees of freedom. Include the possibility that conformational dynamics may be coupled to complex electronic processes or chemical reactions, where quantum mechanical (QM) methods are needed, and this task becomes extremely daunt- ing. Currently, whenever accurate computations of biomolecular systems are essential, the tool of choice is hybrid quantum mechanical / molecular mechanical (QM/MM) calculations, however, the application of these techniques to free energy simulations (FES) is far from common. Herein, we aim to develop a set of robust, efficient, and accurate new techniques that will make the application of QM/MM FES nearly routine. These methods will be subsequently ap- plied to study two classes of biomolecular applications that present extreme challenges to current techniques. Namely, the accurate computation of (1) absolute pKa as a function of ligand binding and reaction (e.g., accounting for tran- sient interactions), and (2) free energy differences of binding as a function of tautomerism. The scientific results will be closely tied to activities aimed at improving access to these advanced techniques.