生物大分子的量子和经典的理论计算研究
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摘要
生物大分子的动力学模拟计算研究随着计算机计算能力的快速发展越来越受到人们的重视。分子动力学(Molecular Dynamics, MD)模拟计算可以通过力场得到生物大分子在原子水平上的相互作用,重现分子运动的微观过程,可以得到生物大分子构象变化的详细信息以及系统静态和动态的动力学性质和热力学性质。在近几十年里,分子动力学模拟已经成为研究生物大分子的一个重要工具和活跃的前沿课题。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。
热休克蛋白(heat shock proteins, Hsps)是1962年由遗传学家Ritossa发现。热休克蛋白是一类在生物进化过程中高度保守的蛋白质。近年来的研究认为Hsp90是许多癌基因通路的重要组成部分,在肿瘤细胞的成长过程中有着非常重要的作用,Hsp90已成为抗肿瘤药物的新靶点,Hsp90及其抑制剂是目前抗肿瘤研究的热点和前沿。
4BH、2E1和2D9是基于吡唑而设计的Hsp90抑制剂。2E1由4BH的位置P1上添加乙基乙酰胺(ethylacetamide)基团而形成,在位置P2用甲磺酰基-苯基(methylsulfonyl-benzene)基团替代了原有基团抑制剂4BH变为抑制剂2D9。两个取代都包含了疏水基团—烷基和苯基,这可能是导致疏水相互作用加强的原因,本论文目的是评价两个取代基团对结合自由能的影响。
本论文中,我们对4BH-Hsp90,2E1-Hsp90,2D9-Hsp90三种复合物做了2ns的动力学模拟,结果显示,三种复合物的RMSD几乎相同,我们用MM-PBSA方法计算了三种复合物的结合自由能,结果显示,范德华作用是抑制剂与蛋白相互作用的主要驱动力,抑制剂与每个残基的相互作用谱显示2D9中甲磺酰基-苯基
(methylsulfonyl-benzene)替代导致抑制剂2D9与热休克蛋白产生一个新的且比较重要的作用区。通过构效关系的分析发现,P1和P2位置的替代使2E1和2D9比4BH更有利于与热休克蛋白结合。这些结果为开发更高效抗癌药物提供了有价值的信息。
获得性免疫缺陷综合症(acquired immunodeficiency syndrome, AIDS)简称艾滋病,主要由I型人类免疫缺陷病毒(Human immunodeficiency virus I,HIV-1)引起。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(reversetranscriptase, RT)、蛋白酶(protease, PR)和整合酶(intergrase, IN)。其中蛋白酶是一个具有C2对称性的同源二聚体,每一条肽链由99个氨基酸组成,它的功能是在病毒生命周期中把HIV-1加工为能感染宿主细胞的成熟病毒颗粒,HIV-1蛋白酶中Asp25/Asp25'的质子化状态对于蛋白酶抑制剂的研发以及氨基酸变异对抗药性的影响有重要意义,HIV-1蛋白酶已成为治疗艾滋病药物的重要靶点之一。因此针对这一靶点的药物设计在目前和将来都是相关理论研究的热点领域。
本文还研究了HIV-1蛋白酶抑制剂P1/P1’位置的苄基上一系列氟取代抑制剂的结构活性关系。BE4, BE5和BE6是三个分别在P1/P1’位置的苄基上2,4-、2,3-和2,5-氟取代形成的具有对称性结构的蛋白酶抑制剂。在三个抑制剂中,P1/P1’位置的疏水性苄基和P2/P2’位置的基团2-茚烷醇分别与HIV-1蛋白酶的疏水性口袋相结合。本文对抑制剂BE4、BE5和BE6与HIV-1蛋白酶的复合物分别进行了2ns的分子动力学模拟,模拟过程中位于蛋白酶残基Ile50/Ile50’和抑制剂间的结晶水分子Wat301维持的很好,Wat301分别与残基Ile50/Ile50’和抑制剂形成了稳定的氢键,构建起抑制剂与HIV-1蛋白酶相互作用的桥梁。用MM-PBSA方法计算了三个抑制剂与HIV-1蛋白酶的结合自由能,所获得的结合自由能预测值的排序与实验值的排序吻合得很好。同时,使用GBSA方法得到的能量分解表明,对结合能做出重要贡献的残基形成了以Ala28、Ile50、Ile84、Ala28’、Ile50’和Ile84’为中心6个相互作用群,并且三个抑制剂以相同的作用模式与HIV-1蛋白酶结合,抑制剂与蛋白酶的作用模式为新型蛋白酶抑制剂的设计提供一些理论上的指导。
GRL02031(031,(3aS,5R,6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl[(1S,2R)-1-benzyl-2-hydroxy-3-([(4-methoxyphenyl)sulfonyl]{[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)propyl]carbamate)是最新研制的有较好抗变异能力的抑制HIV-1病毒的药物。本论文中,我们用动力学模拟计算并结合自由能计算的方法研究了HIV-1蛋白酶中Asp25/Asp25'的不同质子化状态对于PR-031相互作用的影响。在PR-031的复合物中,抑制剂GRL02031分别与Asp25/Asp25'形成氢键,,PR与抑制剂GRL02031的相互作用受到两个天冬氨酸残基质子化状态的影响,然而天冬氨酸残基的质子化状态取决于抑制剂的结构以及复合物所处的环境,PR-031复合物的晶体结构中没有提供有关质子化的信息。天冬氨酸质子化态的确定有助于相关药物的设计,有助于HIV-1 PR的变异对抑制剂GRL02031抗药性影响的理论研究。
本研究对PR-031复合物的四种最可能的质子化态进行了5ns的分子动力学模拟,并用MM- PBSA方法计算了PR-031复合物在各种质子化态下的结合自由能,同时用GBSA方法计算了抑制剂GRL02031与蛋白酶各残基的相互作用能。结果显示,不同的质子化态对动力学特征、结合自由能以及PR-031作用机制有较大的影响。综合分析表明A链中Asp25的OD2的质子化是最为可能的质子化态。氢键分析表明不同的质子化态对水分子所起的桥梁作用也有一定的影响。这些研究结果能够对设计更高效的蛋白酶抑制剂以及抗变异药物的研究有理论上的指导意义。
本论文的主要工作可分三部分:第一部分,研究了Hsp90与三个吡唑类抑制剂的作用机制;第二部分,研究了HIV-1蛋白酶与P1/P1’位置的苄基上氟位置不同抑制剂的构效关系;第三部分,研究了Asp25/Asp25'的不同质子化状态对HIV-1蛋白酶和抑制剂GRL02031相互作用的影响。
Computational simulation of the dynamics of biological macromolecules is drawing increasing attention as the processing capacity of computers grows rapidly. By analyzing the dynamics of electromagnetic fields, simulated computations can reproduce microscopic processes of molecular movement, yielding detailed information about the conformational changes of macromolecules, revealing interactions between macromolecules on the atomic level, and predicting quantitatively the mechanical and thermodynamic properties of a microscopic system at rest and in action. During the past few decades, molecular dynamics (MD) simulations have become an important tool and active forefront in the study of biological molecules. Notably, accurate prediction of free energy changes has facilitated understanding of the structure-activity relationship of macromolecules, providing the basis for rational drug design.
First discovered by FM Ritossa in the 1960s, heat shock proteins (Hsps) are a class of highly conserved proteins across biological taxa. Recent findings indicate that Hsp90 is a critical component in many oncogenic pathways, playing an important role in carcinogenesis. Consequently, Hsp90 has emerged as a promising target for chemotherapy of tumors. Studies of Hsp90 and its inhibitors is a leading edge in anticancer research.
Three pyrazole-based inhibitors of Hsp90, namely, 4BH, 2E1, and 2D9, were analyzed in this study. 2E1 is formed by appending an ethylamido group onto the P1 position of 4BH, while a methylsulphonylbenzyl substituent at position P2 turns 4BH into 2D9. Both substituents include a hydrophobic group, alkyl or phenyl, which may result in enhanced hydrophobic interactions. One purpose of this work is to assess the effects of these two substituents on binding free energy.
Five-nanosecond MD simulations were performed on the 4BH-Hsp90, 2E1-Hsp90, and 2D9-Hsp90 complexes. It turned out that the RMSD values of the three complexes were nearly the same. Calculation of binding free energy by the MM-PBSA method demonstrated that van der Waals forces were primarily responsible for driving the binding of the inhibitors to Hsp90. Detailed inhibitor–residue interaction spectra revealed a new and important site of interaction between 2D9 and the Hsp due to the methylsulphonulbenzyl substituent. Structure-affinity analyses showed that substitution at P1 and P2 facilitated binding of 2E1 and 2D9 to Hsp compared with 4BH. These data may assist in designing new potent drugs to combat cancer.
Acquired immunodeficiency syndrome (AIDS) is a disease primarily caused by the type 1 Human Immunodeficiency Virus (HIV-1). There are three key enzymes in the replication of the virus, namely, reverse transcriptase (RT), protease (PR), and intergrase (IN). The protease is a homodimer with C2 symmetry, each peptide consisting of 99 amino acids. It functions in the maturation phase of the viral life cycle to produce infectious virion particles. The enzyme has become an important target in anti-AIDS chemotherapy. Since it is an aspartate protease, protonation states of Asp25/Asp25' in the active site is significant in the binding of inhibitors and in determining the effects of amino acid mutations on drug resistance. Development of protease inhibitors remains an active area of theoretical research.
The structure-activity relationship of three related inhibitors of the HIV-1 protease, namely, BE4, BE5, and BE6, were analyzed. The inhibitors have C2 symmetry, with distinctively positioned fluorine substitutions on two symmetrical benzyloxy groups. The hydrophobic benzyloxy groups at P1/P1’and the 2-indanol groups at P2/P2’bind hydrophobic pockets in the protease. Two-nanosecond MD simulations were performed on the complexes formed of an inhibitor and the protease. The crystallization water between Ile50/Ile50’and the inhibitor, Wat301, was well maintained in the simulated processes. The stable hydrogen bonds between the Ile50/Ile50’residues, Wat301, and the inhibitor effectively mediated enzyme-inhibitor binding. The values of binding free energy between each of the three inhibitors and the enzyme as predicted with MM-PBSA were in line with empirical findings. Simultaneous energy decomposition with the GBSA method revealed that all residues that contributed significantly to the binding energy formed six interaction groups around Ala28, Ile50, Ile84, Ala28, Ile50’, and Ile84’. Moreover, the three inhibitors bound the protease in the same pattern. The pattern of interactions between inhibitors and the protease may provide theoretical guidance for designing new inhibitors.
GRL02031(031,(3aS,5R,6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl[(1S,2R)-1- benzyl-2-hydroxy-3-([(4-methoxyphenyl)sulfonyl]{[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)propyl]carbamate) is new drug to inhibit HIV-1 with improved ability to resist viral mutations. MD simulations in combination with calculations of binding free energy were performed to assess the effect of the various protonation states of Asp25/Asp25’on the binding free energy between HIV-1 protease and the 031 inhibitor. In the PR-031 complex, the inhibitor formed separate hydrogen bonds with Asp25 and Asp25’. Protonation states of both aspartate residues affected the enzyme-inhibitor interactions. However, the protonation states were dependent on the structure of the inhibitor and the environment around the complex. No information about protonation states was found in the crystal structures of the PR-031 complex.
Five-nanosecond MD simulations were performed to investigate the four most probable protonation states of the PR-031 complex. Binding energy of the complex with various protonation states were calculated using the MM-PBSA method. The GBSA method was used to calculate the interactions between inhibitor 031 and individual amino acid residues of the protease. The results showed that different protonation states significantly affected the dynamic properties, binding free energy, and the mechanisms of PR-031 interactions. Comprehensive analyses indicated that the OD2 protonation state of Asp25 in chain A was the most probable state. Moreover, analysis of hydrogen bonding showed that different protonation states also had some influence on the water bridge. The study provides theoretical guidance for designing high affinity inhibitors and understanding mutation-induced drug resistance.
The dissertation primarily consists of three sections. The first section studied the mechanisms of interaction between Hsp90 and its three pyrazole-based inhibitors. The second section studied the structure-activity relationship between the HIV-1 protease and its inhibitors with different fluorine positions on the benzyloxy groups. The third section studied the effect of different protonation states of the aspartate residues in the HIV-1 protease on its interaction with the GRL02031 inhibitor.
热休克蛋白(heat shock proteins, Hsps)是1962年由遗传学家Ritossa发现。热休克蛋白是一类在生物进化过程中高度保守的蛋白质。近年来的研究认为Hsp90是许多癌基因通路的重要组成部分,在肿瘤细胞的成长过程中有着非常重要的作用,Hsp90已成为抗肿瘤药物的新靶点,Hsp90及其抑制剂是目前抗肿瘤研究的热点和前沿。
4BH、2E1和2D9是基于吡唑而设计的Hsp90抑制剂。2E1由4BH的位置P1上添加乙基乙酰胺(ethylacetamide)基团而形成,在位置P2用甲磺酰基-苯基(methylsulfonyl-benzene)基团替代了原有基团抑制剂4BH变为抑制剂2D9。两个取代都包含了疏水基团—烷基和苯基,这可能是导致疏水相互作用加强的原因,本论文目的是评价两个取代基团对结合自由能的影响。
本论文中,我们对4BH-Hsp90,2E1-Hsp90,2D9-Hsp90三种复合物做了2ns的动力学模拟,结果显示,三种复合物的RMSD几乎相同,我们用MM-PBSA方法计算了三种复合物的结合自由能,结果显示,范德华作用是抑制剂与蛋白相互作用的主要驱动力,抑制剂与每个残基的相互作用谱显示2D9中甲磺酰基-苯基
(methylsulfonyl-benzene)替代导致抑制剂2D9与热休克蛋白产生一个新的且比较重要的作用区。通过构效关系的分析发现,P1和P2位置的替代使2E1和2D9比4BH更有利于与热休克蛋白结合。这些结果为开发更高效抗癌药物提供了有价值的信息。
获得性免疫缺陷综合症(acquired immunodeficiency syndrome, AIDS)简称艾滋病,主要由I型人类免疫缺陷病毒(Human immunodeficiency virus I,HIV-1)引起。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(reversetranscriptase, RT)、蛋白酶(protease, PR)和整合酶(intergrase, IN)。其中蛋白酶是一个具有C2对称性的同源二聚体,每一条肽链由99个氨基酸组成,它的功能是在病毒生命周期中把HIV-1加工为能感染宿主细胞的成熟病毒颗粒,HIV-1蛋白酶中Asp25/Asp25'的质子化状态对于蛋白酶抑制剂的研发以及氨基酸变异对抗药性的影响有重要意义,HIV-1蛋白酶已成为治疗艾滋病药物的重要靶点之一。因此针对这一靶点的药物设计在目前和将来都是相关理论研究的热点领域。
本文还研究了HIV-1蛋白酶抑制剂P1/P1’位置的苄基上一系列氟取代抑制剂的结构活性关系。BE4, BE5和BE6是三个分别在P1/P1’位置的苄基上2,4-、2,3-和2,5-氟取代形成的具有对称性结构的蛋白酶抑制剂。在三个抑制剂中,P1/P1’位置的疏水性苄基和P2/P2’位置的基团2-茚烷醇分别与HIV-1蛋白酶的疏水性口袋相结合。本文对抑制剂BE4、BE5和BE6与HIV-1蛋白酶的复合物分别进行了2ns的分子动力学模拟,模拟过程中位于蛋白酶残基Ile50/Ile50’和抑制剂间的结晶水分子Wat301维持的很好,Wat301分别与残基Ile50/Ile50’和抑制剂形成了稳定的氢键,构建起抑制剂与HIV-1蛋白酶相互作用的桥梁。用MM-PBSA方法计算了三个抑制剂与HIV-1蛋白酶的结合自由能,所获得的结合自由能预测值的排序与实验值的排序吻合得很好。同时,使用GBSA方法得到的能量分解表明,对结合能做出重要贡献的残基形成了以Ala28、Ile50、Ile84、Ala28’、Ile50’和Ile84’为中心6个相互作用群,并且三个抑制剂以相同的作用模式与HIV-1蛋白酶结合,抑制剂与蛋白酶的作用模式为新型蛋白酶抑制剂的设计提供一些理论上的指导。
GRL02031(031,(3aS,5R,6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl[(1S,2R)-1-benzyl-2-hydroxy-3-([(4-methoxyphenyl)sulfonyl]{[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)propyl]carbamate)是最新研制的有较好抗变异能力的抑制HIV-1病毒的药物。本论文中,我们用动力学模拟计算并结合自由能计算的方法研究了HIV-1蛋白酶中Asp25/Asp25'的不同质子化状态对于PR-031相互作用的影响。在PR-031的复合物中,抑制剂GRL02031分别与Asp25/Asp25'形成氢键,,PR与抑制剂GRL02031的相互作用受到两个天冬氨酸残基质子化状态的影响,然而天冬氨酸残基的质子化状态取决于抑制剂的结构以及复合物所处的环境,PR-031复合物的晶体结构中没有提供有关质子化的信息。天冬氨酸质子化态的确定有助于相关药物的设计,有助于HIV-1 PR的变异对抑制剂GRL02031抗药性影响的理论研究。
本研究对PR-031复合物的四种最可能的质子化态进行了5ns的分子动力学模拟,并用MM- PBSA方法计算了PR-031复合物在各种质子化态下的结合自由能,同时用GBSA方法计算了抑制剂GRL02031与蛋白酶各残基的相互作用能。结果显示,不同的质子化态对动力学特征、结合自由能以及PR-031作用机制有较大的影响。综合分析表明A链中Asp25的OD2的质子化是最为可能的质子化态。氢键分析表明不同的质子化态对水分子所起的桥梁作用也有一定的影响。这些研究结果能够对设计更高效的蛋白酶抑制剂以及抗变异药物的研究有理论上的指导意义。
本论文的主要工作可分三部分:第一部分,研究了Hsp90与三个吡唑类抑制剂的作用机制;第二部分,研究了HIV-1蛋白酶与P1/P1’位置的苄基上氟位置不同抑制剂的构效关系;第三部分,研究了Asp25/Asp25'的不同质子化状态对HIV-1蛋白酶和抑制剂GRL02031相互作用的影响。
Computational simulation of the dynamics of biological macromolecules is drawing increasing attention as the processing capacity of computers grows rapidly. By analyzing the dynamics of electromagnetic fields, simulated computations can reproduce microscopic processes of molecular movement, yielding detailed information about the conformational changes of macromolecules, revealing interactions between macromolecules on the atomic level, and predicting quantitatively the mechanical and thermodynamic properties of a microscopic system at rest and in action. During the past few decades, molecular dynamics (MD) simulations have become an important tool and active forefront in the study of biological molecules. Notably, accurate prediction of free energy changes has facilitated understanding of the structure-activity relationship of macromolecules, providing the basis for rational drug design.
First discovered by FM Ritossa in the 1960s, heat shock proteins (Hsps) are a class of highly conserved proteins across biological taxa. Recent findings indicate that Hsp90 is a critical component in many oncogenic pathways, playing an important role in carcinogenesis. Consequently, Hsp90 has emerged as a promising target for chemotherapy of tumors. Studies of Hsp90 and its inhibitors is a leading edge in anticancer research.
Three pyrazole-based inhibitors of Hsp90, namely, 4BH, 2E1, and 2D9, were analyzed in this study. 2E1 is formed by appending an ethylamido group onto the P1 position of 4BH, while a methylsulphonylbenzyl substituent at position P2 turns 4BH into 2D9. Both substituents include a hydrophobic group, alkyl or phenyl, which may result in enhanced hydrophobic interactions. One purpose of this work is to assess the effects of these two substituents on binding free energy.
Five-nanosecond MD simulations were performed on the 4BH-Hsp90, 2E1-Hsp90, and 2D9-Hsp90 complexes. It turned out that the RMSD values of the three complexes were nearly the same. Calculation of binding free energy by the MM-PBSA method demonstrated that van der Waals forces were primarily responsible for driving the binding of the inhibitors to Hsp90. Detailed inhibitor–residue interaction spectra revealed a new and important site of interaction between 2D9 and the Hsp due to the methylsulphonulbenzyl substituent. Structure-affinity analyses showed that substitution at P1 and P2 facilitated binding of 2E1 and 2D9 to Hsp compared with 4BH. These data may assist in designing new potent drugs to combat cancer.
Acquired immunodeficiency syndrome (AIDS) is a disease primarily caused by the type 1 Human Immunodeficiency Virus (HIV-1). There are three key enzymes in the replication of the virus, namely, reverse transcriptase (RT), protease (PR), and intergrase (IN). The protease is a homodimer with C2 symmetry, each peptide consisting of 99 amino acids. It functions in the maturation phase of the viral life cycle to produce infectious virion particles. The enzyme has become an important target in anti-AIDS chemotherapy. Since it is an aspartate protease, protonation states of Asp25/Asp25' in the active site is significant in the binding of inhibitors and in determining the effects of amino acid mutations on drug resistance. Development of protease inhibitors remains an active area of theoretical research.
The structure-activity relationship of three related inhibitors of the HIV-1 protease, namely, BE4, BE5, and BE6, were analyzed. The inhibitors have C2 symmetry, with distinctively positioned fluorine substitutions on two symmetrical benzyloxy groups. The hydrophobic benzyloxy groups at P1/P1’and the 2-indanol groups at P2/P2’bind hydrophobic pockets in the protease. Two-nanosecond MD simulations were performed on the complexes formed of an inhibitor and the protease. The crystallization water between Ile50/Ile50’and the inhibitor, Wat301, was well maintained in the simulated processes. The stable hydrogen bonds between the Ile50/Ile50’residues, Wat301, and the inhibitor effectively mediated enzyme-inhibitor binding. The values of binding free energy between each of the three inhibitors and the enzyme as predicted with MM-PBSA were in line with empirical findings. Simultaneous energy decomposition with the GBSA method revealed that all residues that contributed significantly to the binding energy formed six interaction groups around Ala28, Ile50, Ile84, Ala28, Ile50’, and Ile84’. Moreover, the three inhibitors bound the protease in the same pattern. The pattern of interactions between inhibitors and the protease may provide theoretical guidance for designing new inhibitors.
GRL02031(031,(3aS,5R,6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl[(1S,2R)-1- benzyl-2-hydroxy-3-([(4-methoxyphenyl)sulfonyl]{[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)propyl]carbamate) is new drug to inhibit HIV-1 with improved ability to resist viral mutations. MD simulations in combination with calculations of binding free energy were performed to assess the effect of the various protonation states of Asp25/Asp25’on the binding free energy between HIV-1 protease and the 031 inhibitor. In the PR-031 complex, the inhibitor formed separate hydrogen bonds with Asp25 and Asp25’. Protonation states of both aspartate residues affected the enzyme-inhibitor interactions. However, the protonation states were dependent on the structure of the inhibitor and the environment around the complex. No information about protonation states was found in the crystal structures of the PR-031 complex.
Five-nanosecond MD simulations were performed to investigate the four most probable protonation states of the PR-031 complex. Binding energy of the complex with various protonation states were calculated using the MM-PBSA method. The GBSA method was used to calculate the interactions between inhibitor 031 and individual amino acid residues of the protease. The results showed that different protonation states significantly affected the dynamic properties, binding free energy, and the mechanisms of PR-031 interactions. Comprehensive analyses indicated that the OD2 protonation state of Asp25 in chain A was the most probable state. Moreover, analysis of hydrogen bonding showed that different protonation states also had some influence on the water bridge. The study provides theoretical guidance for designing high affinity inhibitors and understanding mutation-induced drug resistance.
The dissertation primarily consists of three sections. The first section studied the mechanisms of interaction between Hsp90 and its three pyrazole-based inhibitors. The second section studied the structure-activity relationship between the HIV-1 protease and its inhibitors with different fluorine positions on the benzyloxy groups. The third section studied the effect of different protonation states of the aspartate residues in the HIV-1 protease on its interaction with the GRL02031 inhibitor.
引文
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