BIOMOLECULAR INTERACTIONS AND ENZYMATIC PROCESSES

提出了一个多方面的研究项目，旨在发展生物物理相互作用和酶催化反应在溶液中的理论表征能力。 理论方法集中在酶系统的计算机模拟，使用结合量子力学和分子力学（QM/MM）方法。 为了提高计算方法的准确性，将在从头算分子轨道水平上发展一种广义杂化轨道（GHO）方法来处理量子力学和经典碎片之间的共价键划分。 此外，一个从头算混合分子轨道-价键（MOVB）方法正在开发中的溶液和酶促反应的溶剂反应坐标处理。 这种方法超越了传统的经验价键（EVB）的方法，经验力场被用来校准参数的非绝热反应物和产品的状态。QM/MM方法是研究酶催化反应机理的一个重要方法。 特别是，人蛋白酪氨酸磷酸酶1B（PTP 1B）的脱磷酸化反应和角鲨烯环化酶的角鲨烯到hopene的转换将进行研究，以提供底物结合，反应机制，和自由能的酶促过程中的配置文件的详细了解。 PTP 1B存在于多种人体组织中，在乳腺癌中过表达，在胰岛素敏感性和燃料代谢中起主要作用。 对这些酶反应的计算研究可以帮助更好地设计用于治疗癌症、糖尿病和肥胖症的降胆固醇药物和治疗剂。此外，碳酸酐酶II的活性位点中的叠氮离子的振动群体弛豫将被研究，以了解酶的反应性和蛋白质的动力学和波动之间的关系。 振动弛豫时间和振动频率-频率相关函数的计算将有助于解释最近的激光光谱实验。

A multi-faceted research project aimed at developing the capacity for theoretical characterization of biophysical interactions and enzyme-catalyzed reactions in solution is proposed. The theoretical approach centers on computer simulations of enzymatic systems, using combined quantum mechanical and molecular mechanical (QM/MM) methods. To increase the accuracy of the computational methods, a generalized hybrid orbital (GHO) approach will be developed at the ab initio molecular orbital level to treat the covalent bond division between quantum- mechanical and classical fragments. In addition, an ab initio mixed molecular orbital-valence bond (MOVB) method is being developed to treat the solvent reaction coordinate for solution and enzymatic reactions. This approach goes beyond the traditional empirical valence bond (EVB) method where empirical force fields are used to calibrate parameters for the diabatic reactant and product states. A major thrust is to investigate the mechanism of enzyme- catalyzed reactions using combined QM/MM methods. In particular, the dephosphorylation reaction of human protein tyrosine phosphatase 1B (PTP1B) and the squalene to hopene conversion by squalene cyclase will be studied to provided a detailed understanding of substrate binding, reaction mechanism, and free energy profiles for the enzymatic process. PTP1B is found in a variety of human tissues, which is overexpressed in breast-cancer and has a major role in both insulin sensitivity and fuel metabolism. Computational studies of these enzyme reactions can help to better design cholesterol-lowering drugs and therapeutic agents for treatment of cancer, diabetes and obesity. In addition, the vibrational population relaxation of an azide ion in the active site of carbonic anhydrase II will be investigated to understand the relationship between enzyme reactivity and protein dynamics and fluctuation. The vibrational relaxation time and vibrational frequency-frequency correlation function will be computed to help interpret recent laser spectroscopic experiments.