BIOMOLECULAR INTERACTIONS AND ENZYMATIC PROCESSES

生物分子相互作用和酶促过程

• 批准号: 6636041
• 负责人: JIALI GAO
• 金额: $ 19.53万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636041
• 关键词: bacteriorhodopsins; carbonate dehydratase; catalyst; computer program /software; computer simulation; enzyme activity; enzyme structure; intermolecular interaction; ionic bond; mathematical model; method development; model design /development; molecular dynamics; molecular polarity; molecular rearrangement; photochemistry; physical model; protein structure function; protein tyrosine phosphatase; quantum chemistry; solutions; structural biology

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.

提出了一个多面研究项目，旨在发展溶液中生物物理相互作用和酶催化反应的理论表征的能力。 理论方法使用合并的量子机械和分子机械（QM/mm）方法以酶促系统的计算机模拟为中心。 为了提高计算方法的准确性，将在从头算分子轨道水平上开发广义的杂化轨道（GHO）方法，以治疗量子机械和经典片段之间的共价键分裂。 此外，正在开发一种从头静脉静脉混合分子轨道键（MOVB）方法来处理溶剂反应坐标的溶液和酶促反应。 这种方法超出了传统的经验价键（EVB）方法，在该方法中，经验力场被用于校准糖尿病反应物和产物态的参数。一个主要的推力是使用QM/mm合并的方法研究酶催化反应的机理。 特别是，将研究人类蛋白酪氨酸磷酸酶1B（PTP1B）的去磷酸化反应和小鼠环酶转化为霍普烯的霍金烯转化，以详细了解酶促过程的底物结合，反应机制和自由能曲线。 PTP1B在多种人体组织中发现，该组织在乳腺癌中过表达，并且在胰岛素敏感性和燃料代谢中具有重要作用。 这些酶反应的计算研究可以帮助更好地设计降低胆固醇的药物和治疗癌症，糖尿病和肥胖症的治疗剂。此外，将研究二氮化酶II的叠氮化物离子II中叠氮化物离子的振动种群松弛，以了解酶反应性与蛋白质动力学和波动之间的关系。 将计算振动松弛时间和振动频率相关函数，以帮助解释最近的激光光谱实验。