分子模拟研究几类重要蛋白质与底物的相互作用
摘要
蛋白质是生物信息学研究的一个重要对象,本文利用分子力学和分子动力学方法,研究了三种蛋白质与底物的相互作用,为进一步药物设计奠定了理论基础。主要内容包括:
1.采用大分子对接方法构建了SSH2与P-cofilin的三维复合物模型,通过对复合物及两个单体蛋白的动力学模拟来揭示蛋白与底物结合的特异性。计算结果表明:复合物的形成使磷酸化丝切蛋白N末端柔性降低,SSH2在结合底物前后有着相似的分子内部运动。自由能分析显示分子力学能对蛋白复合物整体相互作用贡献最大,库仑静电相互作用对结合部位起主导作用。
2.通过分子动力学模拟方法研究吡唑基吡咯类抑制剂与ERK2的结合特异性及抑制机理。计算结果表明ERK2与三个不同的抑制剂结合,其运动模式的相似性很高,抑制剂对结合位点的空间利用的越好,其抑制效果越强。自由能分析显示库仑静电能是抑制剂对ERK2起作用的最关键因素,ERK2与抑制剂之间形成的氢键数越多,抑制效果越好,并且抑制剂柔性适当提高也有利于抑制活性的提高。
3.通过对人类8位氧化鸟嘌呤DNA糖基化酶1与DNA底物复合物的分子动力学模拟研究,揭示了底物的结合使hOgg1的内部运动受到一定限制,Ser147和底物碱基上的8位氧原子对Lys249侧链N去质子化起关键作用,Asp268不参与Lys249的氨基去质子化过程。结果为进一步研究hOgg1与损伤DNA的反应机理提供了有力的理论依据。
From the nineties of the 20th century, with the development of computer science as well as the human genome project implementation, bioinformatics has been developed rapidly. Protein is an indispensable research object in bioinformatics, therefore, computer simulation of proteins has become a well-established and important research area. Via molecular modeling can build the three-dimensional model of proteins, to research the structure characteristics of the macromolecules, analyze the interaction between the protein and substrate, describe protein biochemistry functions, thus molecular simulation has already become a powerful tool for biology experiments and drug design. In this thesis, we have carried out molecular simulation technology to study protein-protein, protein-inhibitor and protein-DNA interactions. The computer simulations of the protein and substrate interactions may understand some problems that can not been solved in the experiment. The simulation results can support the further studies on them and direct the design of new inhibitors and drugs. The main results are summarised as follows:
1. Theoretical study on human slingshot phosphatase 2 interacting with phospho-cofilin.
Human cofilin is a member of the actin-depolymerizing factor (ADF)/cofilin (A/C) family, which plays an important role in severing and depolymerization of actin filament in cells. Slingshot (SSH) is a kind of dual specificity protein tyrosine phosphatases (DSPs), it can dephosphorylate cofilin at phosphoserine 3 to disrupt actin reorganization. The three dimension structures of the two monomeric proteins have been determined in experiment, but the complex structure of the two proteins has not been reported. Therefore, the interaction specificities between SSH2 and P-confilin are still unknown. In this study, based on experimental data, the complex structure of SSH2 and P-cofilin has been constructed by macromolecular docking method. Then the conformational changes of the two proteins and the binding specificity between SSH2 and P-cofilin are revealed through using molecular dynamics simulation. The results indicate that the formation of the complex combined with the flexibility of N-terminal in P-cofilin being lower. The molecular motions are similar whether SSH2 binds substrate or not. The free energy analysis indicates that the molecular mechanics energy is the largest contribution to the complex interaction on the whole, while the coulomb electrostatic interaction plays a dominant role on the active local. The major interaction mode is through hydrogen bond, salt bridge and hydrophobic interactions. The largest electrostatic attraction take place between residues Arg258, Lys253 and phospho-serine, the strongest electrostatic repulsion happens between Asp221 and Sep3.
2. Theoretical studies on the interaction between extracelluar signal-regulated protein kinase 2 and pyrazolylpyrrole inhibitors.
The extracelluar signal-regulated protein kinase 2 (ERK2) is a member of mitogen-activated protein (MAP) kinases, which is expressed to varying extents in all tissues, including terminally differentiated cells. It has been reported that ERK2 plays a key role in the negative growth control of breast cancer cells and hyperexpression of ERK2 in human breast cancer. Therefore, the research about the inhibitors of ERK2 has been developed widely. The pyrazolylpyrrole compounds have been reported previously as effective ATP competitive inhibitors of ERK, but the problem that the different structure of inhibitor affects the structure of receptor is still unknown. In this study, based on the crystal complexes of ERK2-pyrazolylpyrrole as initial structures, the binding specificity and inhibition mechanics are investigated through molecular dynamics simulations. The results indicate that the motional modes among ERK2 with three different inhibitors have good similarity. The more stable the conformation is, the better the inhibition effect is. The result of binding free energy is according with the trend in experiment, showing that coulomb interaction energy plays a key role in the binding interaction between ERK2 and inhibitor. The increasing of the hydrogen bonds number is favorable to the improvement of the inhibitory potency. And the high flexibility of inhibitor is also good for the inhibitory interaction.
3. Theoretical studies on human 8-oxoguanine glycosylase 1 interacting with 8-oxoguanine lesion DNA.
The repair of damaged DNA is an important guarantee, which can maintain the accuracy and integrity of genetic information. There are many repair enzymes to achieve this work in organisms. Human 8-oxoguanine glycosylase 1 is a member of HhH-GPD superfamily, which can repair the damaged DNA of 8-oxoG specially. In the first step of hOgg1 repairing the damaged nucleobase, there is problem about the disputation of Lys249 deprotonating. In this study, we constructed the complex of hOgg1 and 8-oxoG DNA based on crystal structure. Then the flexibilities of the protein in the different states are investigated by using molecular dynamics simulation. And the interactions among the key residues are analyzed, which reveal the deprotonating probability of the catalytic residue Lys249 and the role of Asp268 during the simulation. The results show that: a) The residue Asp268 only play a role of capping at the N-terminal end of anαhelix, not take part in the process of deprotonating the Lys249 amine group. b) The residue Lys249 is a key catalytic residue, as a nucleophile, which must be deprotonated firstly. c) The residues Ser147 and the 8-oxygen atom of substrate may be the key residues, which can deprotonate the proton of the side-chain amine group in Lys249.
1.采用大分子对接方法构建了SSH2与P-cofilin的三维复合物模型,通过对复合物及两个单体蛋白的动力学模拟来揭示蛋白与底物结合的特异性。计算结果表明:复合物的形成使磷酸化丝切蛋白N末端柔性降低,SSH2在结合底物前后有着相似的分子内部运动。自由能分析显示分子力学能对蛋白复合物整体相互作用贡献最大,库仑静电相互作用对结合部位起主导作用。
2.通过分子动力学模拟方法研究吡唑基吡咯类抑制剂与ERK2的结合特异性及抑制机理。计算结果表明ERK2与三个不同的抑制剂结合,其运动模式的相似性很高,抑制剂对结合位点的空间利用的越好,其抑制效果越强。自由能分析显示库仑静电能是抑制剂对ERK2起作用的最关键因素,ERK2与抑制剂之间形成的氢键数越多,抑制效果越好,并且抑制剂柔性适当提高也有利于抑制活性的提高。
3.通过对人类8位氧化鸟嘌呤DNA糖基化酶1与DNA底物复合物的分子动力学模拟研究,揭示了底物的结合使hOgg1的内部运动受到一定限制,Ser147和底物碱基上的8位氧原子对Lys249侧链N去质子化起关键作用,Asp268不参与Lys249的氨基去质子化过程。结果为进一步研究hOgg1与损伤DNA的反应机理提供了有力的理论依据。
From the nineties of the 20th century, with the development of computer science as well as the human genome project implementation, bioinformatics has been developed rapidly. Protein is an indispensable research object in bioinformatics, therefore, computer simulation of proteins has become a well-established and important research area. Via molecular modeling can build the three-dimensional model of proteins, to research the structure characteristics of the macromolecules, analyze the interaction between the protein and substrate, describe protein biochemistry functions, thus molecular simulation has already become a powerful tool for biology experiments and drug design. In this thesis, we have carried out molecular simulation technology to study protein-protein, protein-inhibitor and protein-DNA interactions. The computer simulations of the protein and substrate interactions may understand some problems that can not been solved in the experiment. The simulation results can support the further studies on them and direct the design of new inhibitors and drugs. The main results are summarised as follows:
1. Theoretical study on human slingshot phosphatase 2 interacting with phospho-cofilin.
Human cofilin is a member of the actin-depolymerizing factor (ADF)/cofilin (A/C) family, which plays an important role in severing and depolymerization of actin filament in cells. Slingshot (SSH) is a kind of dual specificity protein tyrosine phosphatases (DSPs), it can dephosphorylate cofilin at phosphoserine 3 to disrupt actin reorganization. The three dimension structures of the two monomeric proteins have been determined in experiment, but the complex structure of the two proteins has not been reported. Therefore, the interaction specificities between SSH2 and P-confilin are still unknown. In this study, based on experimental data, the complex structure of SSH2 and P-cofilin has been constructed by macromolecular docking method. Then the conformational changes of the two proteins and the binding specificity between SSH2 and P-cofilin are revealed through using molecular dynamics simulation. The results indicate that the formation of the complex combined with the flexibility of N-terminal in P-cofilin being lower. The molecular motions are similar whether SSH2 binds substrate or not. The free energy analysis indicates that the molecular mechanics energy is the largest contribution to the complex interaction on the whole, while the coulomb electrostatic interaction plays a dominant role on the active local. The major interaction mode is through hydrogen bond, salt bridge and hydrophobic interactions. The largest electrostatic attraction take place between residues Arg258, Lys253 and phospho-serine, the strongest electrostatic repulsion happens between Asp221 and Sep3.
2. Theoretical studies on the interaction between extracelluar signal-regulated protein kinase 2 and pyrazolylpyrrole inhibitors.
The extracelluar signal-regulated protein kinase 2 (ERK2) is a member of mitogen-activated protein (MAP) kinases, which is expressed to varying extents in all tissues, including terminally differentiated cells. It has been reported that ERK2 plays a key role in the negative growth control of breast cancer cells and hyperexpression of ERK2 in human breast cancer. Therefore, the research about the inhibitors of ERK2 has been developed widely. The pyrazolylpyrrole compounds have been reported previously as effective ATP competitive inhibitors of ERK, but the problem that the different structure of inhibitor affects the structure of receptor is still unknown. In this study, based on the crystal complexes of ERK2-pyrazolylpyrrole as initial structures, the binding specificity and inhibition mechanics are investigated through molecular dynamics simulations. The results indicate that the motional modes among ERK2 with three different inhibitors have good similarity. The more stable the conformation is, the better the inhibition effect is. The result of binding free energy is according with the trend in experiment, showing that coulomb interaction energy plays a key role in the binding interaction between ERK2 and inhibitor. The increasing of the hydrogen bonds number is favorable to the improvement of the inhibitory potency. And the high flexibility of inhibitor is also good for the inhibitory interaction.
3. Theoretical studies on human 8-oxoguanine glycosylase 1 interacting with 8-oxoguanine lesion DNA.
The repair of damaged DNA is an important guarantee, which can maintain the accuracy and integrity of genetic information. There are many repair enzymes to achieve this work in organisms. Human 8-oxoguanine glycosylase 1 is a member of HhH-GPD superfamily, which can repair the damaged DNA of 8-oxoG specially. In the first step of hOgg1 repairing the damaged nucleobase, there is problem about the disputation of Lys249 deprotonating. In this study, we constructed the complex of hOgg1 and 8-oxoG DNA based on crystal structure. Then the flexibilities of the protein in the different states are investigated by using molecular dynamics simulation. And the interactions among the key residues are analyzed, which reveal the deprotonating probability of the catalytic residue Lys249 and the role of Asp268 during the simulation. The results show that: a) The residue Asp268 only play a role of capping at the N-terminal end of anαhelix, not take part in the process of deprotonating the Lys249 amine group. b) The residue Lys249 is a key catalytic residue, as a nucleophile, which must be deprotonated firstly. c) The residues Ser147 and the 8-oxygen atom of substrate may be the key residues, which can deprotonate the proton of the side-chain amine group in Lys249.
引文
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