HIV-1蛋白酶与抑制剂相互作用的理论计算研究
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摘要
随着人们对人类基因作用的认识,以功能基因组学和蛋白质组学为主要研究对象的后基因组时代已经到来。蛋白质结构与功能关系的研究以及这些研究的实际应用,已经成为蛋白质学科研究的重要组成部分。一些病毒蛋白在病毒的生命周期中起到关键作用,而病毒蛋白与药物的相互作用和识别是有效抑制蛋白功能和治疗疾病的重要途径之一。因此,蛋白质受体与药物的相互作用研究对于药物与蛋白受体的作用机制的理解与蛋白质结构和功能的认识具有重要的意义,并为新药靶点的发现和药物设计提供一定的理论基础。药物与受体的相互作用和识别研究一直是生命科学和药物学领域研究的前沿和热点。本文所进行的人类免疫缺陷病毒(HIV-1)蛋白酶与抑制剂相互作用的理论计算研究为抗艾滋病新药的设计提供了理论指导。
艾滋病的流行严重威胁着人类生命健康,针对艾滋病的药物设计是目前各国投入巨资研究的热点领域。多年以来,HIV-1蛋白酶已经成为研发抗HIV新药的一个重要靶点。HIV-1蛋白酶的三维晶体结构是一个具有C2对称性的同质二聚体,每一条肽链均由99个氨基酸组成。在HIV的生命周期中,HIV-1蛋白酶功能是把HIV病毒加工为成熟的、能感染宿主细胞的病毒性颗粒。HIV-1蛋白酶抑制剂与蛋白酶结合可以抑制蛋白酶的活性,阻断艾滋病毒的复制过程,达到治疗艾滋病的目的。因而,研究HIV-1蛋白酶与抑制剂有效识别的作用机制对于针对蛋白酶的抗HIV药物的设计具有重要的意义。
由于实验测定蛋白质复合物结构存在较大的困难,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(Molecular dynamics, MD)和自由能计算等分子模拟方法已经成为研究HIV-1蛋白酶与其抑制剂的相互作用机制及其动态过程的重要手段。基于残基的能量分解能够从原子层次上研究和解释HIV-1蛋白酶与其抑制剂的识别作用机制,以动力学模拟轨迹为基础的氢键动力学分析有助于研究HIV-1蛋白酶与抑制剂的结合专一性,这为以蛋白酶为靶标的抗HIV药物的设计提供了理论上的指导。
在HIV-1蛋白酶与抑制剂的复合物中,由于两个天冬氨酸(Asp25和Asp25′)之间存在强烈的静电排斥作用,所以Asp25和Asp25′的质子化态是否合理对抑制剂与HIV-1蛋白酶结合的稳定性有很大影响。Asp25和Asp25′的不同的质子化态取决于蛋白酶抑制剂的结构和抑制剂与蛋白酶复合物所处的具体环境,但是X-射线晶格实验又不能确定Asp25和Asp25′的质子化态。所以我们使用动力学模拟和自由能计算取代传统的pKa方法研究了抑制剂BEA369和HIV-1蛋白酶复合物中Asp25和Asp25′的质子化态,结果表Asp25和Asp25′的质子化状态对复合物的动力学行为、结合自由能和抑制剂-蛋白酶相互作用谱产生强烈的影响。Asp25/Asp25′的质子化导致了Asp25和Asp25′所带电荷的变化,反过来,这些电荷的变化会影响氢键作用、静电相互作用和极性溶剂化能,这已经为我们的计算研究所证实。总而言之,在所检查的四个质子化态中,Asp25的单质子化最适合于目前所研究的复合物,这个研究能够为BEA369以及类似药物同蛋白酶的结合自由能计算提供有利的贡献,也能够为高亲和能抗艾滋病药物的设计提供理论上的启示。
由于抗药性变异的出现和临床药物的副作用,严重限制了目前所使用药物的治疗疗效。因此,一些具有改良特性的HIV-1蛋白酶抑制剂也正在研发中。本文采用分子动力学模拟、自由能计算和氢键动力学分析研究了氟取代抑制剂的作用和功能。结果表明:单氟取代抑制剂与非氟取代抑制剂(BEB)产生了类似的动力学行为,而双氟取代抑制剂所产生的动力学行为却有明显的不同。使用MM-PBSA方法进行的结合自由能计算表明:范德华作用能驱动了这类抑制剂与HIV蛋白酶的结合,而且氟取代导致了抑制剂与蛋白酶的范德华作用能的增加。使用GBSA方法计算的抑制剂与蛋白酶的相互作用谱表明5个氟取代抑制剂能够与HIV-1蛋白酶中的保守残基相互作用,这有利于提高抑制剂与蛋白酶的结合。基于动力学模拟的氢键动力学分析也证明氟取代对氢键产生较大的影响,与保守残基形成的氢键有利于提高抑制剂的抗病毒活性。所以氟取代可以作为一种策略来设计高效的抗艾滋病毒抑制剂。
抗药性变异严重限制了目前临床所使用药物的药效,它已经成为艾滋病医学治疗过程中所面临的最大挑战。变异对药物抗药机理的阐述有助于研究能够消除抗药性的新型HIV蛋白酶抑制剂。由于单轨迹的MM-PBSA方法忽略了构象变化(键长和键角等)对结合自由能的贡献,又因为变异有可能导致蛋白酶构象的变化,所以采用分离轨迹的MM-PBSA方法计算了抑制剂和变异蛋白酶复合物的结合自由能。研究结果表明气相中静电相互作用能和范德华作用能的减少导致了变异D30N对TMC-114的抗药性,而对于I50V而言,静电能的下降以及极性溶剂化能的增加驱动了I50V对TMC-114的抗药性。同时来自分离动力学模拟方案的自由能计算表明变异D30N和I50V产生了更为刚性的复合物结构。本文利用结构与亲和能的关系分析研究了抑制剂TMC-114与蛋白酶的作用模式以及变异D30N和I50V对TMC-114抗药机制。在三个复合物中,对结和自由能做出主要贡献的残基来自Gly27,Ala28/Ala28′,Asp30′(Asn30′),Ile50/Ile50′或者Val50/Val50′和Ile84/Ile84′。研究表明对抑制剂与HIV-1蛋白酶结合有利的作用主要分为四种类型:氢键、C-H…π相互作用、C-H…O相互作用和C-H…H-C相互作用。PRD30N/TMC114和PRI50V /TMC-114与WT/TMC-114间的结构亲和能关系的比较揭示了D30N和I50V对TMC-114的抗药机制。在TMC-114与Asn30′侧链间所形成氢键的丢失驱动了D30N对TMC-114的抗药性,而I50V对TMC-114的抗药性是由TMC-114与残基Val50′和Asp30′间极性溶剂化能的增加导致的。利用结构与亲和能关系的分析对变异所产生的抗药性进行了定量的和力学的解释,而且与实验分析相一致。这个研究有助于理解变异的本质,能为高效蛋白酶抑制的合理设计提供理论上的指导。
论文共分为七章:第一章为前言部分,简单介绍了HIV蛋白酶的结构、功能作用和目前临床上已经使用的HIV蛋白酶抑制剂;第二章主要介绍了抑制剂与受体相互作用的常见类型;第三章为理论和方法部分,介绍了所使用的量子理论、分子力学方法、动力学模拟方法和自由能计算方法;第四章使用动力学模拟和自由能计算研究了HIV蛋白酶质子化的功能作用;第五章使用分子动力学模拟、自由能分解和氢键动力学分析研究了氟取代抑制剂的作用;第六章使用分离轨迹的MM-PBSA方法研究了变异D30N和I50V对抑制剂TMC-114的抗药性;第七章对本论文工作的进行了全面总结,并对抑制剂与蛋白酶相互作用的研究方法及能适应变异的药物的研发进行了展望,期望在未来有关的研究中能获得更大的进步。
With insights into the function of Human Genome Project (HGP), the post-genomic era based on the functional genomics and proteomics researches has already come. Studies on the structure-affinity relationship and its actual application are important parts of the proteomics research. Some viral protein molecules play crucial roles in the life activities through recognition and interactions with inhibitors molecules.Therefore, the studies of these interactions between protein receptor and inhibitors are important for understanding interaction mechanism of inhibitors with protein receptor,which will also provide the theory foundation for designing and discovering new drug targets.
The prevalence of AIDS dramatically threatens human life health, which makes the drug design against AIDS as a hot field and many countries are spending huge money on it. Over years, the human immunodeficiency virus type ? aspartic protease has become an important target for the development of new anti-AIDS virus inhibitors. Because HIV-1 protease is responsible for the cleavage of the gag and pol nonfunctional polypeptides into mature and functional HIV viral particles that can infect a host cell in the life cycle of the HIV virus, it is significant to investigate the interaction mechanism of HIV protease with inhibitors for the design of inhibitors targeting HIV protease.
It is difficult to determine a protein complex structure through experimental methods. Recently, with the continuous progress of computers’processing ability, as well as the rapid development and extensive application of theoretical simulation and molecular modeling methods, such as molecular dynamics (MD) simulation, molecular docking and free energy computation, have become important tools for exploring protein with receptor. The interaction mechanisms of HIV protease with inhibitors are investigated and explained by using the decomposition of binding free energy based on inhibitor-residue pair at atomic level, which may provide theoretical hint for the design of HIV-1 protease.
Owing to strong electrostatic repulsion between two residues Asp25 and Asp25′in HIV protease-inhibitor complex, correct protonations of Asp25 and Asp25′have strong influence on the stabilities for the binding of inhibitor to HIV-1 protease. Different protonation states of Asp25/Asp25′were found depending on the structure of the PIs and the local environment in which the PI-PR complex locates. However, the hydrogen position in the X-ray structural data is missing and the information about the protonation cannot be directly gained from the X-ray data, which makes studies of the protonation states of Asp25 and Asp25′indispensable. In this work, molecular dynamics simulations combined with the calculation of free energy are carried out to investigate the protonations of Asp25 and Asp25′in HIV protease-BEA369 complex, and the result suggests that the monoprotonation of Asp25 may be the most applicable to the current complex. Our data are helpful to the design of potent HIV-1 protease inhibitors.
Due to drug-resistant mutations and side effects in clinical treatment, the development of improved inhibitors combating HIV virus is required. MD simulation, the decomposition of binding free energy and dynamics analysis of hydrogen bond are applied to investigate the functions of the fluoro-substituted inhibitors. Our results suggest that van der Waals interactions drive the binding of current studied inhibitors to HIV-1 protease and the the fluoro-substitution leads to the increase in van der Waals interaction. The decomposition of free energy and dynamics analysis of hydrogen bond based on the MD simulation show that the fluoro-substituted inhibitors can interact with the conserved residue in the protease, which suggests that the fluoro-substitution assist in the development of potent inhibitors.
Because of drug-resistant mutations and side effect of drugs, the therapeutic success and efficacy of the current inhibitors are highly limited. It is significantly helpful to elucidate the drug-resistant mechanism of mutation for the development new inhibitors that can remove the drug resistance. 3-ns MD simulations combined with the calculation of binding free energy by using the MM-PB/SA method were carried out to analyze the drug resistance of D30N and I50V to TMC-114, and also investigate the binding mechanisms of TMC-114 to the WT, PRD30N and PRI50V. The results suggest that the decrease in the van der Waals energy and electrostatic energy in the gas phase definitively produce the drug resistance of D30N to TMC-114, while for I50V, the decrease in the electrostatic energy mainly drive its drug resistance to TMC-114. The separate MD simulations of the complex, the protein and the inhibitor were performed to investigate the effects of the conformational changes on the binding. The computed strain energies show that mutants D30N and I50V result in more rigid structure of the PR/TMC-114 complex than the WT.
The analyses of the structure-affinity relationship were applied to investigate the binding mode of TMC-114 to the PR and the drug-resistance mechanisms of D30N and I50V to TMC-114. Among three complexes, the favorable interactions come from Gly27, Ala28/Ala28′, Asp30′(Asn30′), Ile50/Ile50′or Val50/Val50′and Ile84/Ile84′. The favorable interactions mainly were produced by four type interaction: the hydrogen bond interaction, the C-H…πinteractions, the C-H…O interactions and the C-H…H-C interactions. The comparisons of the structure-affinity relationship between the PR and mutant PR expose the resistant mechanisms of two mutations to TMC-114. The loss of the hydrogen bond between TMC-114 and the side chain of Asn30′is the main driving force of the resistance of D30N to TMC-114, additionally, the reduction in the van der Waals energy between Ile84 and TMC-114, also contributes slightly to the resistance of D30N to TMC-114. For I50V, the increase in the polar solvation energies between TMC-114 and two residues Val50′and Asp30′definitively drives the resistance of I50V to TMC-114. The analyses of the hydrogen bonds concerning the water molecule Wat301 were done to investigate the effect of Wat301 on the resistance, and the data show that Wat301 hardly contribute the resistance of D30N and I50V to TMC-114. This study provides a quantitative and mechanistic explanation of mutational effect from detailed analyses of the structure-affinity relationship. We expect that this work can provide some helpful insights into the nature of mutational effect and aid the future design of more potent inhibitors.
This thesis consists of seven chapters. In the first chapter, the structure and function of HIV-1 protease and inhibitors used in clinical treatment are introduced. The classes of the interactions between proteins and inhibitors are described in the second chapter. Theories and methods used in the study, including quantum theory, molecular mechanics method, MD simulation and the calculations of free energy, are introduced in the third chapter. From the fourth chapter to the sixth chapter, the computational work and the main computational results are presented. The fourth chapter analyzes the functional role of the protonation in HIV-1 protease. In the fifth chapter, MD simulation and the dynamical analyses of hydrogen bonds are applied to study the functional roles of the fluoro-substituted inhibitors. The drug-resistant mechanisms of D30N and I50V to TMC-114 are explored by using MM-PBSA method of separate trajectory in the sixth chapter. The seventh chapter draws a conclusion for the whole work and views the future development of the study concerning HIV-1 protease and MD simulation.
艾滋病的流行严重威胁着人类生命健康,针对艾滋病的药物设计是目前各国投入巨资研究的热点领域。多年以来,HIV-1蛋白酶已经成为研发抗HIV新药的一个重要靶点。HIV-1蛋白酶的三维晶体结构是一个具有C2对称性的同质二聚体,每一条肽链均由99个氨基酸组成。在HIV的生命周期中,HIV-1蛋白酶功能是把HIV病毒加工为成熟的、能感染宿主细胞的病毒性颗粒。HIV-1蛋白酶抑制剂与蛋白酶结合可以抑制蛋白酶的活性,阻断艾滋病毒的复制过程,达到治疗艾滋病的目的。因而,研究HIV-1蛋白酶与抑制剂有效识别的作用机制对于针对蛋白酶的抗HIV药物的设计具有重要的意义。
由于实验测定蛋白质复合物结构存在较大的困难,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(Molecular dynamics, MD)和自由能计算等分子模拟方法已经成为研究HIV-1蛋白酶与其抑制剂的相互作用机制及其动态过程的重要手段。基于残基的能量分解能够从原子层次上研究和解释HIV-1蛋白酶与其抑制剂的识别作用机制,以动力学模拟轨迹为基础的氢键动力学分析有助于研究HIV-1蛋白酶与抑制剂的结合专一性,这为以蛋白酶为靶标的抗HIV药物的设计提供了理论上的指导。
在HIV-1蛋白酶与抑制剂的复合物中,由于两个天冬氨酸(Asp25和Asp25′)之间存在强烈的静电排斥作用,所以Asp25和Asp25′的质子化态是否合理对抑制剂与HIV-1蛋白酶结合的稳定性有很大影响。Asp25和Asp25′的不同的质子化态取决于蛋白酶抑制剂的结构和抑制剂与蛋白酶复合物所处的具体环境,但是X-射线晶格实验又不能确定Asp25和Asp25′的质子化态。所以我们使用动力学模拟和自由能计算取代传统的pKa方法研究了抑制剂BEA369和HIV-1蛋白酶复合物中Asp25和Asp25′的质子化态,结果表Asp25和Asp25′的质子化状态对复合物的动力学行为、结合自由能和抑制剂-蛋白酶相互作用谱产生强烈的影响。Asp25/Asp25′的质子化导致了Asp25和Asp25′所带电荷的变化,反过来,这些电荷的变化会影响氢键作用、静电相互作用和极性溶剂化能,这已经为我们的计算研究所证实。总而言之,在所检查的四个质子化态中,Asp25的单质子化最适合于目前所研究的复合物,这个研究能够为BEA369以及类似药物同蛋白酶的结合自由能计算提供有利的贡献,也能够为高亲和能抗艾滋病药物的设计提供理论上的启示。
由于抗药性变异的出现和临床药物的副作用,严重限制了目前所使用药物的治疗疗效。因此,一些具有改良特性的HIV-1蛋白酶抑制剂也正在研发中。本文采用分子动力学模拟、自由能计算和氢键动力学分析研究了氟取代抑制剂的作用和功能。结果表明:单氟取代抑制剂与非氟取代抑制剂(BEB)产生了类似的动力学行为,而双氟取代抑制剂所产生的动力学行为却有明显的不同。使用MM-PBSA方法进行的结合自由能计算表明:范德华作用能驱动了这类抑制剂与HIV蛋白酶的结合,而且氟取代导致了抑制剂与蛋白酶的范德华作用能的增加。使用GBSA方法计算的抑制剂与蛋白酶的相互作用谱表明5个氟取代抑制剂能够与HIV-1蛋白酶中的保守残基相互作用,这有利于提高抑制剂与蛋白酶的结合。基于动力学模拟的氢键动力学分析也证明氟取代对氢键产生较大的影响,与保守残基形成的氢键有利于提高抑制剂的抗病毒活性。所以氟取代可以作为一种策略来设计高效的抗艾滋病毒抑制剂。
抗药性变异严重限制了目前临床所使用药物的药效,它已经成为艾滋病医学治疗过程中所面临的最大挑战。变异对药物抗药机理的阐述有助于研究能够消除抗药性的新型HIV蛋白酶抑制剂。由于单轨迹的MM-PBSA方法忽略了构象变化(键长和键角等)对结合自由能的贡献,又因为变异有可能导致蛋白酶构象的变化,所以采用分离轨迹的MM-PBSA方法计算了抑制剂和变异蛋白酶复合物的结合自由能。研究结果表明气相中静电相互作用能和范德华作用能的减少导致了变异D30N对TMC-114的抗药性,而对于I50V而言,静电能的下降以及极性溶剂化能的增加驱动了I50V对TMC-114的抗药性。同时来自分离动力学模拟方案的自由能计算表明变异D30N和I50V产生了更为刚性的复合物结构。本文利用结构与亲和能的关系分析研究了抑制剂TMC-114与蛋白酶的作用模式以及变异D30N和I50V对TMC-114抗药机制。在三个复合物中,对结和自由能做出主要贡献的残基来自Gly27,Ala28/Ala28′,Asp30′(Asn30′),Ile50/Ile50′或者Val50/Val50′和Ile84/Ile84′。研究表明对抑制剂与HIV-1蛋白酶结合有利的作用主要分为四种类型:氢键、C-H…π相互作用、C-H…O相互作用和C-H…H-C相互作用。PRD30N/TMC114和PRI50V /TMC-114与WT/TMC-114间的结构亲和能关系的比较揭示了D30N和I50V对TMC-114的抗药机制。在TMC-114与Asn30′侧链间所形成氢键的丢失驱动了D30N对TMC-114的抗药性,而I50V对TMC-114的抗药性是由TMC-114与残基Val50′和Asp30′间极性溶剂化能的增加导致的。利用结构与亲和能关系的分析对变异所产生的抗药性进行了定量的和力学的解释,而且与实验分析相一致。这个研究有助于理解变异的本质,能为高效蛋白酶抑制的合理设计提供理论上的指导。
论文共分为七章:第一章为前言部分,简单介绍了HIV蛋白酶的结构、功能作用和目前临床上已经使用的HIV蛋白酶抑制剂;第二章主要介绍了抑制剂与受体相互作用的常见类型;第三章为理论和方法部分,介绍了所使用的量子理论、分子力学方法、动力学模拟方法和自由能计算方法;第四章使用动力学模拟和自由能计算研究了HIV蛋白酶质子化的功能作用;第五章使用分子动力学模拟、自由能分解和氢键动力学分析研究了氟取代抑制剂的作用;第六章使用分离轨迹的MM-PBSA方法研究了变异D30N和I50V对抑制剂TMC-114的抗药性;第七章对本论文工作的进行了全面总结,并对抑制剂与蛋白酶相互作用的研究方法及能适应变异的药物的研发进行了展望,期望在未来有关的研究中能获得更大的进步。
With insights into the function of Human Genome Project (HGP), the post-genomic era based on the functional genomics and proteomics researches has already come. Studies on the structure-affinity relationship and its actual application are important parts of the proteomics research. Some viral protein molecules play crucial roles in the life activities through recognition and interactions with inhibitors molecules.Therefore, the studies of these interactions between protein receptor and inhibitors are important for understanding interaction mechanism of inhibitors with protein receptor,which will also provide the theory foundation for designing and discovering new drug targets.
The prevalence of AIDS dramatically threatens human life health, which makes the drug design against AIDS as a hot field and many countries are spending huge money on it. Over years, the human immunodeficiency virus type ? aspartic protease has become an important target for the development of new anti-AIDS virus inhibitors. Because HIV-1 protease is responsible for the cleavage of the gag and pol nonfunctional polypeptides into mature and functional HIV viral particles that can infect a host cell in the life cycle of the HIV virus, it is significant to investigate the interaction mechanism of HIV protease with inhibitors for the design of inhibitors targeting HIV protease.
It is difficult to determine a protein complex structure through experimental methods. Recently, with the continuous progress of computers’processing ability, as well as the rapid development and extensive application of theoretical simulation and molecular modeling methods, such as molecular dynamics (MD) simulation, molecular docking and free energy computation, have become important tools for exploring protein with receptor. The interaction mechanisms of HIV protease with inhibitors are investigated and explained by using the decomposition of binding free energy based on inhibitor-residue pair at atomic level, which may provide theoretical hint for the design of HIV-1 protease.
Owing to strong electrostatic repulsion between two residues Asp25 and Asp25′in HIV protease-inhibitor complex, correct protonations of Asp25 and Asp25′have strong influence on the stabilities for the binding of inhibitor to HIV-1 protease. Different protonation states of Asp25/Asp25′were found depending on the structure of the PIs and the local environment in which the PI-PR complex locates. However, the hydrogen position in the X-ray structural data is missing and the information about the protonation cannot be directly gained from the X-ray data, which makes studies of the protonation states of Asp25 and Asp25′indispensable. In this work, molecular dynamics simulations combined with the calculation of free energy are carried out to investigate the protonations of Asp25 and Asp25′in HIV protease-BEA369 complex, and the result suggests that the monoprotonation of Asp25 may be the most applicable to the current complex. Our data are helpful to the design of potent HIV-1 protease inhibitors.
Due to drug-resistant mutations and side effects in clinical treatment, the development of improved inhibitors combating HIV virus is required. MD simulation, the decomposition of binding free energy and dynamics analysis of hydrogen bond are applied to investigate the functions of the fluoro-substituted inhibitors. Our results suggest that van der Waals interactions drive the binding of current studied inhibitors to HIV-1 protease and the the fluoro-substitution leads to the increase in van der Waals interaction. The decomposition of free energy and dynamics analysis of hydrogen bond based on the MD simulation show that the fluoro-substituted inhibitors can interact with the conserved residue in the protease, which suggests that the fluoro-substitution assist in the development of potent inhibitors.
Because of drug-resistant mutations and side effect of drugs, the therapeutic success and efficacy of the current inhibitors are highly limited. It is significantly helpful to elucidate the drug-resistant mechanism of mutation for the development new inhibitors that can remove the drug resistance. 3-ns MD simulations combined with the calculation of binding free energy by using the MM-PB/SA method were carried out to analyze the drug resistance of D30N and I50V to TMC-114, and also investigate the binding mechanisms of TMC-114 to the WT, PRD30N and PRI50V. The results suggest that the decrease in the van der Waals energy and electrostatic energy in the gas phase definitively produce the drug resistance of D30N to TMC-114, while for I50V, the decrease in the electrostatic energy mainly drive its drug resistance to TMC-114. The separate MD simulations of the complex, the protein and the inhibitor were performed to investigate the effects of the conformational changes on the binding. The computed strain energies show that mutants D30N and I50V result in more rigid structure of the PR/TMC-114 complex than the WT.
The analyses of the structure-affinity relationship were applied to investigate the binding mode of TMC-114 to the PR and the drug-resistance mechanisms of D30N and I50V to TMC-114. Among three complexes, the favorable interactions come from Gly27, Ala28/Ala28′, Asp30′(Asn30′), Ile50/Ile50′or Val50/Val50′and Ile84/Ile84′. The favorable interactions mainly were produced by four type interaction: the hydrogen bond interaction, the C-H…πinteractions, the C-H…O interactions and the C-H…H-C interactions. The comparisons of the structure-affinity relationship between the PR and mutant PR expose the resistant mechanisms of two mutations to TMC-114. The loss of the hydrogen bond between TMC-114 and the side chain of Asn30′is the main driving force of the resistance of D30N to TMC-114, additionally, the reduction in the van der Waals energy between Ile84 and TMC-114, also contributes slightly to the resistance of D30N to TMC-114. For I50V, the increase in the polar solvation energies between TMC-114 and two residues Val50′and Asp30′definitively drives the resistance of I50V to TMC-114. The analyses of the hydrogen bonds concerning the water molecule Wat301 were done to investigate the effect of Wat301 on the resistance, and the data show that Wat301 hardly contribute the resistance of D30N and I50V to TMC-114. This study provides a quantitative and mechanistic explanation of mutational effect from detailed analyses of the structure-affinity relationship. We expect that this work can provide some helpful insights into the nature of mutational effect and aid the future design of more potent inhibitors.
This thesis consists of seven chapters. In the first chapter, the structure and function of HIV-1 protease and inhibitors used in clinical treatment are introduced. The classes of the interactions between proteins and inhibitors are described in the second chapter. Theories and methods used in the study, including quantum theory, molecular mechanics method, MD simulation and the calculations of free energy, are introduced in the third chapter. From the fourth chapter to the sixth chapter, the computational work and the main computational results are presented. The fourth chapter analyzes the functional role of the protonation in HIV-1 protease. In the fifth chapter, MD simulation and the dynamical analyses of hydrogen bonds are applied to study the functional roles of the fluoro-substituted inhibitors. The drug-resistant mechanisms of D30N and I50V to TMC-114 are explored by using MM-PBSA method of separate trajectory in the sixth chapter. The seventh chapter draws a conclusion for the whole work and views the future development of the study concerning HIV-1 protease and MD simulation.
引文
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