蛋白质与配体相互作用机理的分子模拟研究
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摘要
随着人类基因组测序的完成,以功能基因组学和蛋白质组学为主要研究内容的后基因组时代已经到来。蛋白质是生物体的重要组成成分,在各种生命活动过程中起着不可替代的作用。蛋白质的功能是当前生命科学领域的研究热点问题。蛋白质与配体的相互作用和识别是蛋白质发挥其生物功能的重要途径,在各种生命活动中扮演着非常重要的角色,比如基因调控、信号传导、免疫应答等都离不开蛋白质与配体的相互作用。因此,研究蛋白质与配体的相互作用机制对于理解生物体调控机制至关重要。此外,蛋白质与配体作用机制的研究也为基于结构的新药研发提供必要的理论基础。
由于采用实验方法测定蛋白质复合物结构尚存在较大的困难,近年来,随着计算机处理能力的不断增强以及理论模拟方法的迅速发展和广泛应用,分子动力学模拟、分子对接和自由能计算等分子模拟方法已经成为研究蛋白质受体与其配体相互作用机制及其动态过程的重要手段。分子模拟方法为从分子、亚基甚至原子层次上了解生命现象及揭示其本质规律提供了很好的手段,并可为实验结果提供有力的理论支持。随着分子模拟的理论完善及技术的进步,分子模拟方法正越来越多地被用于蛋白质结构-功能关系、蛋白质与配体的相互识别以及药物设计的研究工作当中。
细胞内外物质的交换与转运是维持细胞正常生命活动的重要过程,而周质结合蛋白能够特异性的识别和结合底物,并负责将其运送至细胞膜上相应的受体或转运蛋白,以协助调节营养物质的转运或激活趋化现象。研究周质结合蛋白结合和释放底物的过程对于理解这一生命过程具有非常重要的意义。在本论文中的第3和第4章中,分别以维生素B12结合蛋白和两种亚铁血红素结合蛋白为例,研究了第三类周质结合蛋白的结构-功能关系,并对其与相应底物的相互识别机理做了比较深入的探讨。
自1981年6月发现首例艾滋病患者以来,艾滋病在全球范围内迅速传播,严重威胁着人类的生命和健康。1983年科学家Barre-Sinoussi及其同事首次确认1型人类免疫缺陷病毒(HIV-1)是引起艾滋病(AIDS)的病原体。整合酶是研发抗HIV-1新药的一个重要靶点。在HIV-1的生命周期中,整合酶负责把病毒DNA整合到宿主的基因组中。因此,研究整合酶与DNA和抑制剂的相互作用机理对于抗HIV-1药物的设计和改造具有重要意义。在论文的第5章中,研究了HIV-1整合酶与香豆素类抑制剂NSC158393的结合模式,并对其抑制机理做出了合理的解释;在第6章中,综合考虑实验信息与模拟结果,构建了一个整合酶与DNA的复合物结构,该复合物模型可被用于虚拟筛选或其它基于受体的药物设计工作。
本论文主要工作内容包括以下两部分:
1.第三类周质结合蛋白工作机理的分子模拟研究
(1)维生素B12周质结合蛋白BtuF工作机理的分子模拟研究
在本工作中,利用拉伸分子动力学模拟等方法研究了BtuF的工作机理及其与底物维生素B12之间的相互作用,并利用Jarzynski方程计算出了B12解离过程中的平均力势。鉴于B12在外力作用下从BtuF解离前后的自由能变化较大,说明BtuF-B12复合物结构处于较稳定闭合状态,在天然状态下,BtuF可能需要发生较大的构象变化以促进B12的解离。根据对BtuF-B12复合物主成分分析的结果,发现BtuF展现出明显的“开-合”和“扭转”运动的趋势,这与第一、二类周质结合蛋白所采用的“捕蝇草”工作机制相吻合。最后对BtuF的柔性进行了分析,发现位于B12结合口袋最外侧的Trp44和Gln45在BtuF结合和释放B12的过程中起门控作用。
(2)亚铁血红素周质结合蛋白ShuT和PhuT工作机理的分子模拟研究
模拟结果表明,ShuT和PhuT的柔性比以往认为的要大很多。通过监测ShuT/PhuT的N/C-端结构域之间的距离变化,发现在未与底物结合的情况下,ShuT和PhuT都展现出了较明显的“开-合”运动。此外,根据区域运动分析,发现自由态的ShuT/PhuT的确在模拟中呈现明显的区域性运动,再次说明“开-合”运动可能是ShuT/PhuT所固有的运动模式。根据主成分分析的结果,发现无论是否结合heme,二者都具有“开-合”和“扭转”两种运动的趋势。根据高斯网络模型给出的结果,发现位于ShuT/PhuT的linker的中点附近的残基可能在它们的区域性运动中充当铰链区。根据模拟结果可以推测,ShuT和PhuT可能采用所谓的“捕蝇草”工作机制来结合和释放其底物。
2. HIV-1整合酶与抑制剂相互作用的分子模拟研究
(1) HIV-1整合酶与香豆素类抑制剂NSC158393的结合模式与抑制机理的分子模拟研究
用多构象分子对接方法分别获得了野生型整合酶及W132G、C130S两个突变型整合酶与香豆素类IN抑制剂NSC158393的复合物结构,并用分子动力学模拟对复合物结构进行了优化和修正,最后用MM-GBSA方法找到了结合NSC158393的关键残基。总体来说,NSC158393与128-136肽段结合,但是在三个体系中的具体结合模式各不相同。通过分析野生型IN与NSC158393的复合物的模拟结果,发现NSC158393不但可以影响IN二聚体的稳定性或干扰多聚体的形成,更重要的是,它可以显著地降低140~149功能loop区的柔性。相比于野生型IN,NSC158393不能抑制两个突变性IN的140~149功能loop区的柔性,也不能很好的干扰IN二聚体的稳定性,因此无法有效地抑制整合过程。根据MM-GBSA给出的结果,发现W131、G134和K136这三个残基对于NSC158393的结合至关重要。特别是W131,可能对于NSC158393与整合酶的相互识别是必不可少的。
(2) HIV-1整合酶与DNA复合物的构建及其与二酮酸类抑制剂结合模式的分子模拟研究
在本工作中,综合考虑实验信息和SMD模拟的结果构建了一个IN-DNA复合物模型,并利用分子对接,得到了两组IN抑制剂与IN-DNA复合物的结合模式。根据对接结果发现,尽管骨架结构不同,两组IN抑制剂与IN-DNA复合物的结合模式比较类似:其类二酮酸基团都与Mg2+相互作用,且其卤代苯基团都插入loop区附近的一个疏水口袋中。由此可以推测这两组IN抑制剂的作用机理可能比较相似。根据结合能分解发现,化合物1与T66、D116、F139和I141等氨基酸残基之间有较强的相互作用,而这些氨基酸残基已被证明对于IN催化活性或抑制剂的结合有重要作用。本工作中的主要结论均与之前的实验或模拟工作相符,说明该模型可以为今后的基于受体的IN抑制剂合理设计和改造提供一定帮助。
With the completion of the human genome project, the post-genomic era, which mainly focuses on functional genomics and proteomics, has come. Proteins are important components of organisms,playing indispensable role in many kinds of life processes. The relationship between structure and function of protein is one of the pioneering and hot issues in the current life science researches. The interactions and recognition between protein and ligand is the main way through which does the protein exert its biological functions, playing crucial role in various life activities, such as gene regulation, signal transduction and immune response. Therefore, the study of the interaction mechanism between protein and ligand is of great significance for understanding the regulatory mechanisms of organisms, and also providing necessary theoretical basis for the research and development of new drugs.
Since determining structure of protein complex with experimental approach is still challenging, recently, with the continuous progress in computers’processing ability and the rapid development and extensive application of theoretical simulation, molecular modeling methods, such as molecular dynamics (MD) simulation, molecular docking and free energy computation, have become important tools for exploring the interaction process of protein with its ligand. Molecular modeling not only enables us to understand and reveal the essence of life phenomena in the level of molecule, subunit or even atom, but also provides strong theoretical support to experimental results. With the improvement of molecular modeling theory and technology advances, molecular modeling methods are increasingly being used in the research of protein structure-function relationship, protein-ligand mutual recognition, as well as rational drug design.
Exchange and transport of substances between environment and the inside of a cell is vital for the cell to maintain its normal life activity. Periplasmic binding protein (PBP) can recognize and bind substrate specifically, and is responsible for its delivery to the corresponding receptors or transporter proteins in the cell membrance to help regulate the translocation of nutrients or initiate chemotaxis. Study on the binding and unbinding processes of PBPs is very helpful for us to understand the substances exchange and transport process. As exemplified by the B12 binding protein BtuF and the two heme binding protein ShuT and PhuT, the structure-function relationship and the mutual recognition mechanism of the third class PBPs are thoroughly discussed in Chapter 3 and 4, respectively.
Since was first discovered in June 1981, Acquired Immune Deficiency Syndrome (AIDS) speeded rapidly on a global scale and soon become a serious threat to human life and health. In the year of 1983, Barre-Sinousi and colleagues first identified the human immunodeficiency virus type 1 (HIV-1) as the pathogens of AIDS. HIV-1 integrase (IN) is an important target for the design and development of novel anti-HIV drugs. In the life cycle of HIV, IN is responsible for the integration of viral DNA into the host chromosome. Consequently, the study on the recognition mechanism of IN with inhibitors is important for the design and modification of the anti-HIV drugs. In Chapter 5 of this dissertation, the binding modes of HIV-1 IN with the coumarin-containing IN inhibitor NSC158393 is explored, and the inhibitory mechanism of this inhibitor is explained. In Chapter 6, a complex structure of HIV IN and DNA was constructed and this complex model can be used in virtual screening or other receptor-based drug design. The main content of this dissertation includes the following two parts:
1. Study on the mechanism of the third class preriplasmic binding protein with molecular modeling
(1) Study on the mechanism of the BtuF periplasmic binding protein for vitamin B12 with molecular modeling
In this work, the steered molecular dynamics simulation (SMD) and other molecular modeling methods were employed on the B12-bound BtuF to investigate the energetics and mechanism of BtuF, and a potential of mean force along the postulated vitamin B12 unbinding pathway was constructed through Jarzynski's equation. The large free energy differences of the postulated B12 unbinding process inticates that the B12-bound structure is in a stable closed state and some conformation changes may be necessary to the B12 unbinding. From the result of the principal component analysis, we found that the BtuF-B12 complex shows clear opening-closing and twisting motion tendencies which are consistent with the so-called“Venus-flytrap”mechanism taken by the first and the second periplasmic binding proteins (PBPs). The intrinsic flexibility of BtuF was also explored. Based on these results, it is found that the Trp44-Gln45 pair situated at the mouth of the B12 binding pocket may act as a gate in the B12 binding and unbinding process.
(2) Study on the mechanism of the bacterial periplasmic heme binding proteins ShuT and PhuT with molecular modeling
By performing a series of long time MD simulations on the ShuT and the PhuT, the dynamics properties and functions of the two PBPs were investigated. The flexibilities of the two proteins are much higher than previously assumed. Through monitoring the distance changes between the N/C-terminal domains of ShuT and PhuT, it was found that the two PBPs, when in unbound state, exhibit obvious opening–closing motions. Based on the results of the domain motion analysis, large scale conformational transitions were found in all heme-free runs of ShuT and PhuT, hinting that the domain motions of the two PBPs may be intrinsic. On the basis of the results of the principle component analysis, distinct opening–closing and twisting motion tendencies were observed not only in the heme-free, but also in the heme-bound simulations of the two PBPs. The Gaussian network model was applied in order to analyze the hinge bending regions. The most important bending regions, which may act as hinges, of ShuT and PhuT are all located around the midpoints of their respective linker. In conclusion, the two heme binding protein ShuT and PhuT may also take the so-called“Venus-flytrap”mechanism during the process of capturing and releasing their substrates.
2. Study on the interactions between HIV-1 integrase and inhibitors with molecular modeling
(1) Study on the inhibitory mechanism and binding mode of the coumarin compound NSC158393 to HIV-1 integrase with molecular modeling
In this work, the binding modes of the wild type IN core domain and the two mutants (W132G and C130S) with the 4-hydroxycoumarin compound NSC158393 were first obtained by using the“relaxed complex”molecular docking approach combined with MD simulations, and then the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method was employed to evaluate the key residues in the binding of HIV-1 IN with NSC158393. In principle, NSC158393 binds the 128-136 peptides of IN, however, the specific binding modes for the three systems are various. According to the simulation results for the complex of the wild type IN and the inhibitor, NSC158393 can not only diminish the stability of the IN dimmer and disturb the formation of IN multimers, but also highly affect the flexibility of the functional 140-149 loop. Comparing with the wild type IN, NSC158393 can not effectively affect the flexibility of the functional 140-149 loop in the two mutants, and it can not interfere with the stability of the IN monomers either. Therefore, NSC158393 can not efficiently inhibit the integration process catalyzed by the two mutants. Three key binding residues (W131, K136, and G134) were discovered by energy decomposition calculated with the MM-GBSA method. Characterized by the largest binding affinity, W131 is likely to be indispensable for the binding of NSC158393.
(2) Study on the binding modes of the HIV integrase-DNA complex to some integrase inhibitors with molecular modeling
In the current work, a model for complex of IN and viral DNA was built by combining experimental data with the results of SMD simulation. According to the results of molecular docking, the inhibitors of the second group share a similar binding model with those of the first group, though they have no common scaffold. This suggests that these inhibitors may share a similar inhibitory mechanism. In principle, these compounds interact the Mg2+ ion with their DKA-like moieties and make hydrophobic interactions with a pocket around the functional 140-149 loop with their halogenated-benzene moieties. Finally, the interactions between IN and one of these inhibitors were explored to understand their binding modes. Some key residues for ligand binding, such as T66、D116、F139 and I141, are identified according to the calculation on the interactions, and all of which have been proved to be important for DNA recognition or the catalytic activity of IN. All main findings of this work are in good accordance with previous experiment or simulation works and the newly built model of the IN-DNA complex is helpful for the subsequent research on the design of IN inhibitors.
由于采用实验方法测定蛋白质复合物结构尚存在较大的困难,近年来,随着计算机处理能力的不断增强以及理论模拟方法的迅速发展和广泛应用,分子动力学模拟、分子对接和自由能计算等分子模拟方法已经成为研究蛋白质受体与其配体相互作用机制及其动态过程的重要手段。分子模拟方法为从分子、亚基甚至原子层次上了解生命现象及揭示其本质规律提供了很好的手段,并可为实验结果提供有力的理论支持。随着分子模拟的理论完善及技术的进步,分子模拟方法正越来越多地被用于蛋白质结构-功能关系、蛋白质与配体的相互识别以及药物设计的研究工作当中。
细胞内外物质的交换与转运是维持细胞正常生命活动的重要过程,而周质结合蛋白能够特异性的识别和结合底物,并负责将其运送至细胞膜上相应的受体或转运蛋白,以协助调节营养物质的转运或激活趋化现象。研究周质结合蛋白结合和释放底物的过程对于理解这一生命过程具有非常重要的意义。在本论文中的第3和第4章中,分别以维生素B12结合蛋白和两种亚铁血红素结合蛋白为例,研究了第三类周质结合蛋白的结构-功能关系,并对其与相应底物的相互识别机理做了比较深入的探讨。
自1981年6月发现首例艾滋病患者以来,艾滋病在全球范围内迅速传播,严重威胁着人类的生命和健康。1983年科学家Barre-Sinoussi及其同事首次确认1型人类免疫缺陷病毒(HIV-1)是引起艾滋病(AIDS)的病原体。整合酶是研发抗HIV-1新药的一个重要靶点。在HIV-1的生命周期中,整合酶负责把病毒DNA整合到宿主的基因组中。因此,研究整合酶与DNA和抑制剂的相互作用机理对于抗HIV-1药物的设计和改造具有重要意义。在论文的第5章中,研究了HIV-1整合酶与香豆素类抑制剂NSC158393的结合模式,并对其抑制机理做出了合理的解释;在第6章中,综合考虑实验信息与模拟结果,构建了一个整合酶与DNA的复合物结构,该复合物模型可被用于虚拟筛选或其它基于受体的药物设计工作。
本论文主要工作内容包括以下两部分:
1.第三类周质结合蛋白工作机理的分子模拟研究
(1)维生素B12周质结合蛋白BtuF工作机理的分子模拟研究
在本工作中,利用拉伸分子动力学模拟等方法研究了BtuF的工作机理及其与底物维生素B12之间的相互作用,并利用Jarzynski方程计算出了B12解离过程中的平均力势。鉴于B12在外力作用下从BtuF解离前后的自由能变化较大,说明BtuF-B12复合物结构处于较稳定闭合状态,在天然状态下,BtuF可能需要发生较大的构象变化以促进B12的解离。根据对BtuF-B12复合物主成分分析的结果,发现BtuF展现出明显的“开-合”和“扭转”运动的趋势,这与第一、二类周质结合蛋白所采用的“捕蝇草”工作机制相吻合。最后对BtuF的柔性进行了分析,发现位于B12结合口袋最外侧的Trp44和Gln45在BtuF结合和释放B12的过程中起门控作用。
(2)亚铁血红素周质结合蛋白ShuT和PhuT工作机理的分子模拟研究
模拟结果表明,ShuT和PhuT的柔性比以往认为的要大很多。通过监测ShuT/PhuT的N/C-端结构域之间的距离变化,发现在未与底物结合的情况下,ShuT和PhuT都展现出了较明显的“开-合”运动。此外,根据区域运动分析,发现自由态的ShuT/PhuT的确在模拟中呈现明显的区域性运动,再次说明“开-合”运动可能是ShuT/PhuT所固有的运动模式。根据主成分分析的结果,发现无论是否结合heme,二者都具有“开-合”和“扭转”两种运动的趋势。根据高斯网络模型给出的结果,发现位于ShuT/PhuT的linker的中点附近的残基可能在它们的区域性运动中充当铰链区。根据模拟结果可以推测,ShuT和PhuT可能采用所谓的“捕蝇草”工作机制来结合和释放其底物。
2. HIV-1整合酶与抑制剂相互作用的分子模拟研究
(1) HIV-1整合酶与香豆素类抑制剂NSC158393的结合模式与抑制机理的分子模拟研究
用多构象分子对接方法分别获得了野生型整合酶及W132G、C130S两个突变型整合酶与香豆素类IN抑制剂NSC158393的复合物结构,并用分子动力学模拟对复合物结构进行了优化和修正,最后用MM-GBSA方法找到了结合NSC158393的关键残基。总体来说,NSC158393与128-136肽段结合,但是在三个体系中的具体结合模式各不相同。通过分析野生型IN与NSC158393的复合物的模拟结果,发现NSC158393不但可以影响IN二聚体的稳定性或干扰多聚体的形成,更重要的是,它可以显著地降低140~149功能loop区的柔性。相比于野生型IN,NSC158393不能抑制两个突变性IN的140~149功能loop区的柔性,也不能很好的干扰IN二聚体的稳定性,因此无法有效地抑制整合过程。根据MM-GBSA给出的结果,发现W131、G134和K136这三个残基对于NSC158393的结合至关重要。特别是W131,可能对于NSC158393与整合酶的相互识别是必不可少的。
(2) HIV-1整合酶与DNA复合物的构建及其与二酮酸类抑制剂结合模式的分子模拟研究
在本工作中,综合考虑实验信息和SMD模拟的结果构建了一个IN-DNA复合物模型,并利用分子对接,得到了两组IN抑制剂与IN-DNA复合物的结合模式。根据对接结果发现,尽管骨架结构不同,两组IN抑制剂与IN-DNA复合物的结合模式比较类似:其类二酮酸基团都与Mg2+相互作用,且其卤代苯基团都插入loop区附近的一个疏水口袋中。由此可以推测这两组IN抑制剂的作用机理可能比较相似。根据结合能分解发现,化合物1与T66、D116、F139和I141等氨基酸残基之间有较强的相互作用,而这些氨基酸残基已被证明对于IN催化活性或抑制剂的结合有重要作用。本工作中的主要结论均与之前的实验或模拟工作相符,说明该模型可以为今后的基于受体的IN抑制剂合理设计和改造提供一定帮助。
With the completion of the human genome project, the post-genomic era, which mainly focuses on functional genomics and proteomics, has come. Proteins are important components of organisms,playing indispensable role in many kinds of life processes. The relationship between structure and function of protein is one of the pioneering and hot issues in the current life science researches. The interactions and recognition between protein and ligand is the main way through which does the protein exert its biological functions, playing crucial role in various life activities, such as gene regulation, signal transduction and immune response. Therefore, the study of the interaction mechanism between protein and ligand is of great significance for understanding the regulatory mechanisms of organisms, and also providing necessary theoretical basis for the research and development of new drugs.
Since determining structure of protein complex with experimental approach is still challenging, recently, with the continuous progress in computers’processing ability and the rapid development and extensive application of theoretical simulation, molecular modeling methods, such as molecular dynamics (MD) simulation, molecular docking and free energy computation, have become important tools for exploring the interaction process of protein with its ligand. Molecular modeling not only enables us to understand and reveal the essence of life phenomena in the level of molecule, subunit or even atom, but also provides strong theoretical support to experimental results. With the improvement of molecular modeling theory and technology advances, molecular modeling methods are increasingly being used in the research of protein structure-function relationship, protein-ligand mutual recognition, as well as rational drug design.
Exchange and transport of substances between environment and the inside of a cell is vital for the cell to maintain its normal life activity. Periplasmic binding protein (PBP) can recognize and bind substrate specifically, and is responsible for its delivery to the corresponding receptors or transporter proteins in the cell membrance to help regulate the translocation of nutrients or initiate chemotaxis. Study on the binding and unbinding processes of PBPs is very helpful for us to understand the substances exchange and transport process. As exemplified by the B12 binding protein BtuF and the two heme binding protein ShuT and PhuT, the structure-function relationship and the mutual recognition mechanism of the third class PBPs are thoroughly discussed in Chapter 3 and 4, respectively.
Since was first discovered in June 1981, Acquired Immune Deficiency Syndrome (AIDS) speeded rapidly on a global scale and soon become a serious threat to human life and health. In the year of 1983, Barre-Sinousi and colleagues first identified the human immunodeficiency virus type 1 (HIV-1) as the pathogens of AIDS. HIV-1 integrase (IN) is an important target for the design and development of novel anti-HIV drugs. In the life cycle of HIV, IN is responsible for the integration of viral DNA into the host chromosome. Consequently, the study on the recognition mechanism of IN with inhibitors is important for the design and modification of the anti-HIV drugs. In Chapter 5 of this dissertation, the binding modes of HIV-1 IN with the coumarin-containing IN inhibitor NSC158393 is explored, and the inhibitory mechanism of this inhibitor is explained. In Chapter 6, a complex structure of HIV IN and DNA was constructed and this complex model can be used in virtual screening or other receptor-based drug design. The main content of this dissertation includes the following two parts:
1. Study on the mechanism of the third class preriplasmic binding protein with molecular modeling
(1) Study on the mechanism of the BtuF periplasmic binding protein for vitamin B12 with molecular modeling
In this work, the steered molecular dynamics simulation (SMD) and other molecular modeling methods were employed on the B12-bound BtuF to investigate the energetics and mechanism of BtuF, and a potential of mean force along the postulated vitamin B12 unbinding pathway was constructed through Jarzynski's equation. The large free energy differences of the postulated B12 unbinding process inticates that the B12-bound structure is in a stable closed state and some conformation changes may be necessary to the B12 unbinding. From the result of the principal component analysis, we found that the BtuF-B12 complex shows clear opening-closing and twisting motion tendencies which are consistent with the so-called“Venus-flytrap”mechanism taken by the first and the second periplasmic binding proteins (PBPs). The intrinsic flexibility of BtuF was also explored. Based on these results, it is found that the Trp44-Gln45 pair situated at the mouth of the B12 binding pocket may act as a gate in the B12 binding and unbinding process.
(2) Study on the mechanism of the bacterial periplasmic heme binding proteins ShuT and PhuT with molecular modeling
By performing a series of long time MD simulations on the ShuT and the PhuT, the dynamics properties and functions of the two PBPs were investigated. The flexibilities of the two proteins are much higher than previously assumed. Through monitoring the distance changes between the N/C-terminal domains of ShuT and PhuT, it was found that the two PBPs, when in unbound state, exhibit obvious opening–closing motions. Based on the results of the domain motion analysis, large scale conformational transitions were found in all heme-free runs of ShuT and PhuT, hinting that the domain motions of the two PBPs may be intrinsic. On the basis of the results of the principle component analysis, distinct opening–closing and twisting motion tendencies were observed not only in the heme-free, but also in the heme-bound simulations of the two PBPs. The Gaussian network model was applied in order to analyze the hinge bending regions. The most important bending regions, which may act as hinges, of ShuT and PhuT are all located around the midpoints of their respective linker. In conclusion, the two heme binding protein ShuT and PhuT may also take the so-called“Venus-flytrap”mechanism during the process of capturing and releasing their substrates.
2. Study on the interactions between HIV-1 integrase and inhibitors with molecular modeling
(1) Study on the inhibitory mechanism and binding mode of the coumarin compound NSC158393 to HIV-1 integrase with molecular modeling
In this work, the binding modes of the wild type IN core domain and the two mutants (W132G and C130S) with the 4-hydroxycoumarin compound NSC158393 were first obtained by using the“relaxed complex”molecular docking approach combined with MD simulations, and then the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method was employed to evaluate the key residues in the binding of HIV-1 IN with NSC158393. In principle, NSC158393 binds the 128-136 peptides of IN, however, the specific binding modes for the three systems are various. According to the simulation results for the complex of the wild type IN and the inhibitor, NSC158393 can not only diminish the stability of the IN dimmer and disturb the formation of IN multimers, but also highly affect the flexibility of the functional 140-149 loop. Comparing with the wild type IN, NSC158393 can not effectively affect the flexibility of the functional 140-149 loop in the two mutants, and it can not interfere with the stability of the IN monomers either. Therefore, NSC158393 can not efficiently inhibit the integration process catalyzed by the two mutants. Three key binding residues (W131, K136, and G134) were discovered by energy decomposition calculated with the MM-GBSA method. Characterized by the largest binding affinity, W131 is likely to be indispensable for the binding of NSC158393.
(2) Study on the binding modes of the HIV integrase-DNA complex to some integrase inhibitors with molecular modeling
In the current work, a model for complex of IN and viral DNA was built by combining experimental data with the results of SMD simulation. According to the results of molecular docking, the inhibitors of the second group share a similar binding model with those of the first group, though they have no common scaffold. This suggests that these inhibitors may share a similar inhibitory mechanism. In principle, these compounds interact the Mg2+ ion with their DKA-like moieties and make hydrophobic interactions with a pocket around the functional 140-149 loop with their halogenated-benzene moieties. Finally, the interactions between IN and one of these inhibitors were explored to understand their binding modes. Some key residues for ligand binding, such as T66、D116、F139 and I141, are identified according to the calculation on the interactions, and all of which have been proved to be important for DNA recognition or the catalytic activity of IN. All main findings of this work are in good accordance with previous experiment or simulation works and the newly built model of the IN-DNA complex is helpful for the subsequent research on the design of IN inhibitors.
引文
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