HIV-1蛋白酶与抑制剂相互作用的理论研究
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摘要
获得性免疫缺陷综合症(acquired immunodeficiency syndrome, AIDS)简称艾滋病,主要由Ⅰ型人类免疫缺陷性病毒(Human immunodeficiency virus I,HIV-1)引起,是一种跨种属传播的、死亡率很高的疾病,已成为世界第四大死亡原因,艾滋病在世界范围内的迅速传播严重威胁着人类的生命健康,对其的有效治疗已成为医学界最具挑战性的课题,针对艾滋病的药物设计在目前和将来都是相关理论研究的热点领域。
在HIV-1基因组复制过程中,有三种关键的酶,分别是HIV-1逆转录酶(reverse transcriptase, RT)、蛋白酶(protease, PR)和整合酶(intergrase, IN)。其中PR是一个具有C2对称性的同源二聚体,每一条肽链由99个氨基酸组成,它在病毒生命周期中的功能是把HIV-1加工为能感染宿主细胞的成熟的病毒颗粒,因此PR成为研发治疗艾滋病药物的一个重要靶点。
PR抑制剂(protease inhibitors,PIs)是一些具有抑制PR活性的化合物,其作用机理是模拟肽链与PR的结合部位结合,从而抑制PR的活性,阻断艾滋病毒的复制,因此PIs是一类重要的抗艾滋病药物。本文专门针对PR与PIs的相互作用来进行理论研究,这对于针对PR的抗艾滋病药物的设计和研发具有重要意义。
在过去20多年里,人们针对艾滋病的治疗从理论到实验都做了大量的研究工作,取得了不小的进步。但由于实验测定PR及其PIs复合物结构存在较大的困难,因此这一领域的理论研究显得尤为重要。而计算机数据处理能力的不断增强以及各种理论模拟方法的不断发展和改进,又为理论研究提供了从技术到方法的支持。目前分子动力学(molecular dynamics, MD)模拟和自由能计算已成为研究生物大分子结构、动力学和热力学性质的重要工具。MD模拟不仅可给出生物大分子在原子水平上的运动细节,而且能够提供大分子位置涨落和构象变化的详细信息。准确的自由能预测,可以使我们更好地理解生物大分子的结构和功能关系,为合理的药物设计提供依据。目前分子力学/泊松–玻耳兹曼溶剂可接近表面积(molecular mechanics/Poisson-Boltzman surface area,MM-PBSA)方法是应用很广的一种基于经验方程的自由能计算方法。
本文利用MD模拟和MM-PBSA方法进行PR及其PIs相互作用的理论研究,主要由以下三部分内容组成:
1、BEC和BEG两种PIs与PR相互作用机理的研究
本文选择了两种最近被美国食品药品管理局批准使用的PIs BEC和BEG来进行相关研究,采用的方法是MD模拟结合MM-PBSA方法。我们计算分析了BEC-PR和BEG-PR两种复合物PR主链上的Cα原子在整个MD过程中相对于其原始结构的均方根偏差(root-mean-squared deviation,RMSD)值;进行了两种复合物的晶体结构和MD轨迹中最后1ns平均结构的叠加分析;使用单轨迹拓扑的MM-PBSA方法计算了两种复合物的结合自由能;用自由能分解方法计算了PI-残基相互作用谱线。结果表明:这两种复合物的动力学稳定性是可信的;并且范德华能量是这类PIs与PR结合的主要推动力;对这两种复合物,主要的相互作用来自Gly27、Ala28/Ala28′、Gly49、Ile50/Ile50′和Ile84/Ile84′残基,两种复合物的相互作用能主要由三种类型的相互作用产生:氢键相互作用、C–H…π相互作用和C–H…H–C相互作用,它们在BEC和BEG与PR的结合方面发挥着重要作用,这些相互作用的改进和优化可以极大地推动对抗艾滋病的高效PIs的研究。
2、质子化态在PR-Indinavir复合物中作用的研究
茚地那韦(IDV N-[2(R)-HYDROXY-1(S)-INDANYL]-5-[(2(S)-TERTIARY BUTYLAMINOCARBONYL)- 4(3-PYRIDYLMETHYL) PIPERAZINO]-4(S)-HYDROXY- 2(R)-PHENYLMETHYLPENTANAMIDE )是较早被用来抑制PR的PI,PR和IDV的相互作用受两个天冬氨酸残基质子化态的影响很大,而实验提供的PR-IDV复合物的晶体结构不能直接给出有关质子化的信息,因此,确定PR-IDV复合物中天冬氨酸的质子化态有助于设计与IDV相关的PIs,有助于理论上研究PR的变异对其与IDV结合的影响。本文中我们对PR-IDV复合物的六种可能的质子化态分别进行了5ns的分子动力学模拟,分析了这六种不同的质子化状态对动力学特征和结构的影响,并用MM-PBSA方法计算了PR和IDV在各种质子化状态下的结合自由能。计算结果说明A链的Asp25的OD2的质子化是最为可能的状态。同时,我们对PR-IDV复合物中起媒介作用的水分子与PR-IDV复合物形成的氢键进行了分析,结果表明不同的质子化态对水分子在PR-IDV复合物中所起的媒介作用没有影响。
3、PR与PI TMC114结合口袋内水分子作用的研究
水分子在生物分子的稳定、动力学、功能和识别方面发挥着重要作用,许多研究表明水分子不仅能充当PIs和PR之间的桥梁,而且能稳定PR的结构。TMC114是一种相当有效的阻止PR发挥作用的第二代非肽PIs,在PR与TMC114结合口袋内发现有五个水分子(Wat301、Wat2、Wat5、Wat89和Wat211)。我们分别进行了带有和不带有5个水分子的PR-TMC114复合物的3ns分子动力学模拟,计算了PR主链上的Cα原子在MD轨迹过程中相对于原始最小能量结构的RMSD值,将复合物的晶体结构和MD轨迹最后1ns的平均结构进行叠加,并分析了描述结合特性的氢键。计算结果表明:结合口袋内的水分子可以维持PR-TMC114复合物结构的稳定;Wat301,Wat2和Wat5在MD模拟过程中保持稳定;Wat301可以稳定PR与TMC114柔性区域的结构;与5个水分子有关的氢键引起的约束使得PR的残基和TMC114在模拟过程中在它们的原始位置保持不动。我们期待这一研究可以增进人们对PR-PI复合物中水分子作用的深入了解,并且对高效PIs的设计提供有用的帮助。
Acquired immunodeficiency syndrome, simply called AIDS, is mainly caused by human immunodeficiency virus I, i.e. HIV-1. AIDS is a kind of zoonosis disease with high death rate. It has been the fourth death reason in the world. The rapid prevalence of AIDS in the entire world dramatically threatens human's lives and health. The effective therapeutics of AIDS is a challengeable difficulty and the drug design for it is the hot field for theoretical researches currently and in the future.
In the copy procedure of HIV-1 gene group, there are three kinds of key enzyme, i.e. HIV-1 reverse transcriptase (RT), protease (PR) and intergrase (IN). PR is a homodimer with C2 symmetry, and each polypeptide chain is composed of 99 amino acids. Its function in the life cycle of virus is producting HIV-1 into matural virus particles which can infect host cells, thus PR is an important target for the development of AIDS’drugs.
Protease inhibitors (PIs) are some compounds which can inhibit PR’s activity. Its mechanism is simulating the binding of peptide and PR to inhibit PR’s activity and to prevent the copy of HIV-1. Thus PIs are important anti-AIDS drugs. Theoretical study for the interaction of PR and PIs is performed in this paper, which is essential for the design and development of anti-AIDS drugs.
In the last 20 years, lots of researches for AIDS therapeutics in theory and experiment have been done and made great progress. But there are many difficulties in determining the structures of PR and its PIs in experiment, theoretical study is very important for this field. On the other hand, the increasing of the data-dealing ability of computer and the development of theoretical simulation methods give strong technological and methodical support to the theoretical study. Currently, molecular dynamics (MD) and free energy calculation have become very important tools to study the structures, dynamics and thermodynamic properties for bimolecules. MD simulation can give the motional detail at the atomic level and the detail information of position's draft and construction change. Accurate free energy prediction can make us understand the relationship of bimolecular structure and function, and give accordance to rational drug design. Recently, molecular mechanics/Poisson-Boltzman surface area (MM-PBSA) method is an extensive applicable free energy method based on empirical equation.
In this paper, we use MD simulation and MM-PBSA method to investigate the interaction of PR and its PIs, mainly composed by three parts as following.
1、The study of the interaction mechanisms of PIs BEC and BEG with PR
Two PIs BEC and BEG which were approved by the U.S. Food and Drug Administration recently were selected to investigate the PR-PI interactions with MD simulation and MM-PBSA method. The RMSD values of PR Cαatoms relative to the initial structure through the MD simulations were calculated and analyzed, and the analyses of superimposition of the crystal structures with the average structures of two complexes during the last 1ns of the MD trajectories via backbone atoms were carried out. MM-PBSA method involving the single trajectory protocol was performed to calculate the binding free energies, and the interaction spectra were calculated by the free energy decomposition. The results suggest that the stabilities of the dynamic equilibriums for two complexes are reliable and Van der Waals energies mostly drive the bindings of this class of inhibitors to the PR. For the case of two complexes, the favorable interactions come from Gly27, Ala28/Ala28′, Gly49, Ile50/Ile50′and Ile84/Ile84′. The favorable interactions mainly are produced by the three types of interactions: the hydrogen bond interactions, the C-H…πinteractions and the C-H…H-C interactions. These interactions of BEC and BEG with the PR play important roles in the binding of BEC and BEG to the PR. The improvement and optimization of these interactions may benefit the rational design of potent inhibitors combating AIDS.
2、The study of the role of protonation states in PR-Indinavir complex
Indinavir (IDV) is a PI which is used to combat PR early. The interaction of PI and IDV is effected by the protonation state of Asp25/Asp25′, but the crystal structure determined by the experiment can’t give the information about the protonation directly, so the protonation state of Asp25/Asp25′in PR-IDV complex is important for us to study the binding mechanism and the drug resistance induced by the mutation in theory. 5 ns molecular dynamic simulations have been performed for six possible protonation states, and the influences on dynamics behavior and structure caused by different protonation states were analyzed, and relative binding free energies were calculated by using the MM-PBSA method. The results show that the protonation state of OD2 from Asp25 in chain A is the most possible. The hydrogen bonds between the water molecule that plays a medium role and the PR-IDV complex were also analyzed, and the results show that the different states have not obvious influences on the medium role, which is different from our previous result on PR-BEA369 complex. It was expected that this study could provide a significative help for the high affinity inhibitor design and the mutation induced drug resistance research.
3、The study of functional role of water molecules buried within binding pocket of PR with PI TMC114
Water molecules play an important role in the stability, dynamics, function and recognition of bimolecules. Many studies showed that water molecules not only act as a bridge between PIs and PR, but also stabilize the structure of PR. TMC114 is a next-generation nonpeptidic PI that is extremely potent to inhibit the activation of PR. Five water molecules, i.e. Wat301、Wat2、Wat5、Wat89 and Wat211, have been observed within the binding packet of PR with TMC11. 3 ns MD simulations have been successfully performed for PR-TMC114 complexes, one with five water molecules in the binding packet, and another without. The RMSD values of PR’s Cαatoms relative to the initial structure through the MD simulations were calculated, and the analyses of superimposition of the crystal structure with the average structure during the last 1ns of the MD trajectories via backbone atoms were carried out. The hydrogen bond used to describe the binding specificity was analyzed, too. The results indicate that the water molecules can maintain the stability of the structure of complex PR-TMC114, and Wat301, Wat2 and Wat5 are conserved during MD simulation. Wat301 has an ability to maintain the stability of the flaps and TMC114. The restrictions produced by the hydrogen bonds involved 5 water molecules make the residues and TMC114 stay in their original positions during simulation. We expect that this study can provide a significant insight into the function of water molecules in PR-PI complex, and also give some favorable help for the design of potent PIs.
在HIV-1基因组复制过程中,有三种关键的酶,分别是HIV-1逆转录酶(reverse transcriptase, RT)、蛋白酶(protease, PR)和整合酶(intergrase, IN)。其中PR是一个具有C2对称性的同源二聚体,每一条肽链由99个氨基酸组成,它在病毒生命周期中的功能是把HIV-1加工为能感染宿主细胞的成熟的病毒颗粒,因此PR成为研发治疗艾滋病药物的一个重要靶点。
PR抑制剂(protease inhibitors,PIs)是一些具有抑制PR活性的化合物,其作用机理是模拟肽链与PR的结合部位结合,从而抑制PR的活性,阻断艾滋病毒的复制,因此PIs是一类重要的抗艾滋病药物。本文专门针对PR与PIs的相互作用来进行理论研究,这对于针对PR的抗艾滋病药物的设计和研发具有重要意义。
在过去20多年里,人们针对艾滋病的治疗从理论到实验都做了大量的研究工作,取得了不小的进步。但由于实验测定PR及其PIs复合物结构存在较大的困难,因此这一领域的理论研究显得尤为重要。而计算机数据处理能力的不断增强以及各种理论模拟方法的不断发展和改进,又为理论研究提供了从技术到方法的支持。目前分子动力学(molecular dynamics, MD)模拟和自由能计算已成为研究生物大分子结构、动力学和热力学性质的重要工具。MD模拟不仅可给出生物大分子在原子水平上的运动细节,而且能够提供大分子位置涨落和构象变化的详细信息。准确的自由能预测,可以使我们更好地理解生物大分子的结构和功能关系,为合理的药物设计提供依据。目前分子力学/泊松–玻耳兹曼溶剂可接近表面积(molecular mechanics/Poisson-Boltzman surface area,MM-PBSA)方法是应用很广的一种基于经验方程的自由能计算方法。
本文利用MD模拟和MM-PBSA方法进行PR及其PIs相互作用的理论研究,主要由以下三部分内容组成:
1、BEC和BEG两种PIs与PR相互作用机理的研究
本文选择了两种最近被美国食品药品管理局批准使用的PIs BEC和BEG来进行相关研究,采用的方法是MD模拟结合MM-PBSA方法。我们计算分析了BEC-PR和BEG-PR两种复合物PR主链上的Cα原子在整个MD过程中相对于其原始结构的均方根偏差(root-mean-squared deviation,RMSD)值;进行了两种复合物的晶体结构和MD轨迹中最后1ns平均结构的叠加分析;使用单轨迹拓扑的MM-PBSA方法计算了两种复合物的结合自由能;用自由能分解方法计算了PI-残基相互作用谱线。结果表明:这两种复合物的动力学稳定性是可信的;并且范德华能量是这类PIs与PR结合的主要推动力;对这两种复合物,主要的相互作用来自Gly27、Ala28/Ala28′、Gly49、Ile50/Ile50′和Ile84/Ile84′残基,两种复合物的相互作用能主要由三种类型的相互作用产生:氢键相互作用、C–H…π相互作用和C–H…H–C相互作用,它们在BEC和BEG与PR的结合方面发挥着重要作用,这些相互作用的改进和优化可以极大地推动对抗艾滋病的高效PIs的研究。
2、质子化态在PR-Indinavir复合物中作用的研究
茚地那韦(IDV N-[2(R)-HYDROXY-1(S)-INDANYL]-5-[(2(S)-TERTIARY BUTYLAMINOCARBONYL)- 4(3-PYRIDYLMETHYL) PIPERAZINO]-4(S)-HYDROXY- 2(R)-PHENYLMETHYLPENTANAMIDE )是较早被用来抑制PR的PI,PR和IDV的相互作用受两个天冬氨酸残基质子化态的影响很大,而实验提供的PR-IDV复合物的晶体结构不能直接给出有关质子化的信息,因此,确定PR-IDV复合物中天冬氨酸的质子化态有助于设计与IDV相关的PIs,有助于理论上研究PR的变异对其与IDV结合的影响。本文中我们对PR-IDV复合物的六种可能的质子化态分别进行了5ns的分子动力学模拟,分析了这六种不同的质子化状态对动力学特征和结构的影响,并用MM-PBSA方法计算了PR和IDV在各种质子化状态下的结合自由能。计算结果说明A链的Asp25的OD2的质子化是最为可能的状态。同时,我们对PR-IDV复合物中起媒介作用的水分子与PR-IDV复合物形成的氢键进行了分析,结果表明不同的质子化态对水分子在PR-IDV复合物中所起的媒介作用没有影响。
3、PR与PI TMC114结合口袋内水分子作用的研究
水分子在生物分子的稳定、动力学、功能和识别方面发挥着重要作用,许多研究表明水分子不仅能充当PIs和PR之间的桥梁,而且能稳定PR的结构。TMC114是一种相当有效的阻止PR发挥作用的第二代非肽PIs,在PR与TMC114结合口袋内发现有五个水分子(Wat301、Wat2、Wat5、Wat89和Wat211)。我们分别进行了带有和不带有5个水分子的PR-TMC114复合物的3ns分子动力学模拟,计算了PR主链上的Cα原子在MD轨迹过程中相对于原始最小能量结构的RMSD值,将复合物的晶体结构和MD轨迹最后1ns的平均结构进行叠加,并分析了描述结合特性的氢键。计算结果表明:结合口袋内的水分子可以维持PR-TMC114复合物结构的稳定;Wat301,Wat2和Wat5在MD模拟过程中保持稳定;Wat301可以稳定PR与TMC114柔性区域的结构;与5个水分子有关的氢键引起的约束使得PR的残基和TMC114在模拟过程中在它们的原始位置保持不动。我们期待这一研究可以增进人们对PR-PI复合物中水分子作用的深入了解,并且对高效PIs的设计提供有用的帮助。
Acquired immunodeficiency syndrome, simply called AIDS, is mainly caused by human immunodeficiency virus I, i.e. HIV-1. AIDS is a kind of zoonosis disease with high death rate. It has been the fourth death reason in the world. The rapid prevalence of AIDS in the entire world dramatically threatens human's lives and health. The effective therapeutics of AIDS is a challengeable difficulty and the drug design for it is the hot field for theoretical researches currently and in the future.
In the copy procedure of HIV-1 gene group, there are three kinds of key enzyme, i.e. HIV-1 reverse transcriptase (RT), protease (PR) and intergrase (IN). PR is a homodimer with C2 symmetry, and each polypeptide chain is composed of 99 amino acids. Its function in the life cycle of virus is producting HIV-1 into matural virus particles which can infect host cells, thus PR is an important target for the development of AIDS’drugs.
Protease inhibitors (PIs) are some compounds which can inhibit PR’s activity. Its mechanism is simulating the binding of peptide and PR to inhibit PR’s activity and to prevent the copy of HIV-1. Thus PIs are important anti-AIDS drugs. Theoretical study for the interaction of PR and PIs is performed in this paper, which is essential for the design and development of anti-AIDS drugs.
In the last 20 years, lots of researches for AIDS therapeutics in theory and experiment have been done and made great progress. But there are many difficulties in determining the structures of PR and its PIs in experiment, theoretical study is very important for this field. On the other hand, the increasing of the data-dealing ability of computer and the development of theoretical simulation methods give strong technological and methodical support to the theoretical study. Currently, molecular dynamics (MD) and free energy calculation have become very important tools to study the structures, dynamics and thermodynamic properties for bimolecules. MD simulation can give the motional detail at the atomic level and the detail information of position's draft and construction change. Accurate free energy prediction can make us understand the relationship of bimolecular structure and function, and give accordance to rational drug design. Recently, molecular mechanics/Poisson-Boltzman surface area (MM-PBSA) method is an extensive applicable free energy method based on empirical equation.
In this paper, we use MD simulation and MM-PBSA method to investigate the interaction of PR and its PIs, mainly composed by three parts as following.
1、The study of the interaction mechanisms of PIs BEC and BEG with PR
Two PIs BEC and BEG which were approved by the U.S. Food and Drug Administration recently were selected to investigate the PR-PI interactions with MD simulation and MM-PBSA method. The RMSD values of PR Cαatoms relative to the initial structure through the MD simulations were calculated and analyzed, and the analyses of superimposition of the crystal structures with the average structures of two complexes during the last 1ns of the MD trajectories via backbone atoms were carried out. MM-PBSA method involving the single trajectory protocol was performed to calculate the binding free energies, and the interaction spectra were calculated by the free energy decomposition. The results suggest that the stabilities of the dynamic equilibriums for two complexes are reliable and Van der Waals energies mostly drive the bindings of this class of inhibitors to the PR. For the case of two complexes, the favorable interactions come from Gly27, Ala28/Ala28′, Gly49, Ile50/Ile50′and Ile84/Ile84′. The favorable interactions mainly are produced by the three types of interactions: the hydrogen bond interactions, the C-H…πinteractions and the C-H…H-C interactions. These interactions of BEC and BEG with the PR play important roles in the binding of BEC and BEG to the PR. The improvement and optimization of these interactions may benefit the rational design of potent inhibitors combating AIDS.
2、The study of the role of protonation states in PR-Indinavir complex
Indinavir (IDV) is a PI which is used to combat PR early. The interaction of PI and IDV is effected by the protonation state of Asp25/Asp25′, but the crystal structure determined by the experiment can’t give the information about the protonation directly, so the protonation state of Asp25/Asp25′in PR-IDV complex is important for us to study the binding mechanism and the drug resistance induced by the mutation in theory. 5 ns molecular dynamic simulations have been performed for six possible protonation states, and the influences on dynamics behavior and structure caused by different protonation states were analyzed, and relative binding free energies were calculated by using the MM-PBSA method. The results show that the protonation state of OD2 from Asp25 in chain A is the most possible. The hydrogen bonds between the water molecule that plays a medium role and the PR-IDV complex were also analyzed, and the results show that the different states have not obvious influences on the medium role, which is different from our previous result on PR-BEA369 complex. It was expected that this study could provide a significative help for the high affinity inhibitor design and the mutation induced drug resistance research.
3、The study of functional role of water molecules buried within binding pocket of PR with PI TMC114
Water molecules play an important role in the stability, dynamics, function and recognition of bimolecules. Many studies showed that water molecules not only act as a bridge between PIs and PR, but also stabilize the structure of PR. TMC114 is a next-generation nonpeptidic PI that is extremely potent to inhibit the activation of PR. Five water molecules, i.e. Wat301、Wat2、Wat5、Wat89 and Wat211, have been observed within the binding packet of PR with TMC11. 3 ns MD simulations have been successfully performed for PR-TMC114 complexes, one with five water molecules in the binding packet, and another without. The RMSD values of PR’s Cαatoms relative to the initial structure through the MD simulations were calculated, and the analyses of superimposition of the crystal structure with the average structure during the last 1ns of the MD trajectories via backbone atoms were carried out. The hydrogen bond used to describe the binding specificity was analyzed, too. The results indicate that the water molecules can maintain the stability of the structure of complex PR-TMC114, and Wat301, Wat2 and Wat5 are conserved during MD simulation. Wat301 has an ability to maintain the stability of the flaps and TMC114. The restrictions produced by the hydrogen bonds involved 5 water molecules make the residues and TMC114 stay in their original positions during simulation. We expect that this study can provide a significant insight into the function of water molecules in PR-PI complex, and also give some favorable help for the design of potent PIs.
引文
[1]黄文林等.分子病毒学[M].北京:人民卫生出版社,2002: 392-402.
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