几类重要蛋白质的结构及催化特性的理论研究
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摘要
本文利用分子力学和分子动力学方法,对三种蛋白体系进行了三维结构预测和分子对接的理论研究。主要内容包括:
1.利用同源模建及分子动力学模拟,构建了酯酶Pir7b的空间三维结构,通过Pir7b与活性底物及非活性底物的对接研究,揭示了Pir7b底物基团专一性的原因,并预测一些实验上还未确定,但与底物结合及催化过程中起重要作用的氨基酸残基。
2.通过同源模建和分子动力学模拟,构建了脂肪酶sqEH的空间三维结构。通过序列比对分析,推测出sqEH的催化三联体。进一步对三类环氧化物底物的对接研究表明,sqEH仅能有效的催化芳香类和脂肪类环氧化物,并对R型对映体表现出严格的特异性。
3.通过同源模建和分子动力学模拟,构建了单链抗体scFv2F3的三维结构。经过对活性部位的表面分析,讨论了Ser52作为化学修饰活性位点的重要性,并利用突变得到具有谷胱甘肽过氧化物酶活性的抗体酶Se-scFv2F3的近似物Cys-scFv2F3。通过对Cys52临近残基进行突变,引入一个能增强抗体酶催化活性的催化三联体。进一步对Cys52的解离度计算表明,引入的催化三联体能较好的增强Cys52的解离度,提高其亲核进攻能力,为设计更具催化效力的新型抗体酶提供可靠的理论依据。
Molecular modeling is one of the important methods in computational chemistry, which can be used to build, display, simulate, and analyze molecular strucutures and to calculate properties of these structures. In this thesis, molecular mechanics and molecular dynamics methods are used to build three dimensional models for three enzymes and study their structural properties in detail. Some creative results were obtained from our investigation. The main results are outlined as follows:
1. The 3D structure model of esterase Pir7b was constructed by using homology modeling and molecular dynamics simulations. Three substrates were docking to this protein, two of them were proved to be active, and some critical residues are identified, which have not been confirmed by the experiments. His87 and Leu17 considered as‘oxyanion hole’contribute to initiating the Ser86 nucleophilic attack. Gln187 and Asp139 can form hydrogen bonds with the anilid group to maintain the active binding orientation with the substrates. The docking model can well interpret the specificity of protein Pir7b towards the anilid moiety of the substrates and provide valuable structure information about the ligand binding to protein Pir7b.
2. The 3D structure of a novel epoxide hydrolase from Aspergillus niger SQ-6 (sqEH) was constructed by using homology modeling and molecular dynamics simulations. Based on the 3D model, Asp191, His369 and Glu343 were predicted as catalytic triad. The putative active pocket is a hydrophobic environment and is rich in some important non-polar residues (Pro318, Trp282, Pro319, Pro317 and Phe242). Using three sets of epoxide inhibitors for docking study, the interaction energies of sqEH with each inhibitor are consistent with their inhibitory effects in previous experiments. Moreover, a critical water molecule which closes to the His369 was identified to be an ideal position for the hydrolysis step of the reaction. Two tyrosine residues (Tyr249 and Tyr312) are able to form hydrogen bonds with the epoxide oxygen atom to maintain the initial binding and position of the substrate in the active pocket. These docked complex models can well interpret the substrate specificity of sqEH, which could be relevant for the structural—based design of specific epoxide inhibitors.
3. The single chain antibody scFv2F3 can be converted to selenium-containing Se-scFv2F3 by chemical mutation of the Ser residues. Taking antibody fragment 1NQB as a template, the catalytic domain of scFv2F3 was built by using homology modeling and molecular dynamics (MD) simulations. Based on the 3D model, we discussed the importance of Ser52 as the chemical modification site and redesigned the protein groups nearby Ser52 to introduce a catalytic triad. The following 10ns MD results show that the designed Ser52-Trp29-Gln72 catalytic triad is stable enough and high close to the local structural features of native glutathione peroxidases (GPX). Furthermore, the proton pKa shifts of residue 52 in Se-scFv2F3 model and its modified model were computed by using molecular dynamics free energy simulation (MDFE) to evaluate nucleophilic capability of the catalytic residue. Our results may be useful for creating a new abzyme with higher catalytic efficiency and stability.
1.利用同源模建及分子动力学模拟,构建了酯酶Pir7b的空间三维结构,通过Pir7b与活性底物及非活性底物的对接研究,揭示了Pir7b底物基团专一性的原因,并预测一些实验上还未确定,但与底物结合及催化过程中起重要作用的氨基酸残基。
2.通过同源模建和分子动力学模拟,构建了脂肪酶sqEH的空间三维结构。通过序列比对分析,推测出sqEH的催化三联体。进一步对三类环氧化物底物的对接研究表明,sqEH仅能有效的催化芳香类和脂肪类环氧化物,并对R型对映体表现出严格的特异性。
3.通过同源模建和分子动力学模拟,构建了单链抗体scFv2F3的三维结构。经过对活性部位的表面分析,讨论了Ser52作为化学修饰活性位点的重要性,并利用突变得到具有谷胱甘肽过氧化物酶活性的抗体酶Se-scFv2F3的近似物Cys-scFv2F3。通过对Cys52临近残基进行突变,引入一个能增强抗体酶催化活性的催化三联体。进一步对Cys52的解离度计算表明,引入的催化三联体能较好的增强Cys52的解离度,提高其亲核进攻能力,为设计更具催化效力的新型抗体酶提供可靠的理论依据。
Molecular modeling is one of the important methods in computational chemistry, which can be used to build, display, simulate, and analyze molecular strucutures and to calculate properties of these structures. In this thesis, molecular mechanics and molecular dynamics methods are used to build three dimensional models for three enzymes and study their structural properties in detail. Some creative results were obtained from our investigation. The main results are outlined as follows:
1. The 3D structure model of esterase Pir7b was constructed by using homology modeling and molecular dynamics simulations. Three substrates were docking to this protein, two of them were proved to be active, and some critical residues are identified, which have not been confirmed by the experiments. His87 and Leu17 considered as‘oxyanion hole’contribute to initiating the Ser86 nucleophilic attack. Gln187 and Asp139 can form hydrogen bonds with the anilid group to maintain the active binding orientation with the substrates. The docking model can well interpret the specificity of protein Pir7b towards the anilid moiety of the substrates and provide valuable structure information about the ligand binding to protein Pir7b.
2. The 3D structure of a novel epoxide hydrolase from Aspergillus niger SQ-6 (sqEH) was constructed by using homology modeling and molecular dynamics simulations. Based on the 3D model, Asp191, His369 and Glu343 were predicted as catalytic triad. The putative active pocket is a hydrophobic environment and is rich in some important non-polar residues (Pro318, Trp282, Pro319, Pro317 and Phe242). Using three sets of epoxide inhibitors for docking study, the interaction energies of sqEH with each inhibitor are consistent with their inhibitory effects in previous experiments. Moreover, a critical water molecule which closes to the His369 was identified to be an ideal position for the hydrolysis step of the reaction. Two tyrosine residues (Tyr249 and Tyr312) are able to form hydrogen bonds with the epoxide oxygen atom to maintain the initial binding and position of the substrate in the active pocket. These docked complex models can well interpret the substrate specificity of sqEH, which could be relevant for the structural—based design of specific epoxide inhibitors.
3. The single chain antibody scFv2F3 can be converted to selenium-containing Se-scFv2F3 by chemical mutation of the Ser residues. Taking antibody fragment 1NQB as a template, the catalytic domain of scFv2F3 was built by using homology modeling and molecular dynamics (MD) simulations. Based on the 3D model, we discussed the importance of Ser52 as the chemical modification site and redesigned the protein groups nearby Ser52 to introduce a catalytic triad. The following 10ns MD results show that the designed Ser52-Trp29-Gln72 catalytic triad is stable enough and high close to the local structural features of native glutathione peroxidases (GPX). Furthermore, the proton pKa shifts of residue 52 in Se-scFv2F3 model and its modified model were computed by using molecular dynamics free energy simulation (MDFE) to evaluate nucleophilic capability of the catalytic residue. Our results may be useful for creating a new abzyme with higher catalytic efficiency and stability.
引文
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