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计算方法研究HIV-1蛋白酶及其变异与小分子GRL-0519的相互作用
李高峰1, 扈国栋1,2 , 张晨1,2, 季保华1,2, 王吉华1,2     
1. 德州学院物理与电子信息学院,德州 253023;
2. 德州学院山东省生物物理重点实验室,德州 253023
摘要: 艾滋病病毒在世界范围内的传播,严重地威胁到人们的身心健康.HIV-1蛋白酶的残基变异严重地削弱了药物的治疗效果.为了研究残基变异D30N、I54M和V82A对蛋白酶结合抑制剂GRL-0519的影响,本研究进行了4个30 ns的分子动力学(MD)模拟,并采用溶解相互自由能(SIE)方法计算了蛋白酶和抑制剂的结合能.计算结果表明,极性相互作用不利于变异的蛋白酶结合抑制剂,而对于野生型的蛋白酶(WT),极性相互作用有微弱的贡献,极性相互作用是残基变异抗药性的主要原因,计算得到的总结合能与实验的数据一致.为了说明每个残基在抗药性中的贡献,采用分子力场的方法计算了每一个残基与小分子作用的范德华作用能,并分析了抑制剂与蛋白酶形成的氢键.范德华作用分析表明,V82A残基变异对结合模式的影响较小,相对于WT,D30N有5个残基的范德华贡献差异大于0.4 kcal/mol,I54M残基变异的蛋白酶有6个残基.氢键的分析说明,D30N和I54M变异丢失了几个氢键;范德华作用和氢键的分析结果与SIE的计算结果一致.研究结果为设计新的更有效的抗HIV-1蛋白酶变异的抑制剂提供了理论指导.
关键词: HIV-1蛋白酶     抑制剂     分子动力学模拟     结合自由能    
Study The Interaction Between The HIV-1 Protease and Its Mutations With Inhibitor GRL-0519 by The Computational Method
LI Gao-Feng1, HU Guo-Dong1,2, ZHANG Chen11,2, JI Bao-Hua11,2, WANG Ji-Hua1,2     
1. College of Physics and Electronic Information, Dezhou University, Dezhou 253023, China;
2. Shandong Provincial Key Laboratory of Biophysics, Dezhou University, Dezhou 253023, China
*This work was supported by grants from The National Natural Science Foundation of China (11447004, 61671107), The Natural Science Foundation of Shandong Province (ZR2014JL006) and the Taishan Scholars Program of Shandong province of China
** Corresponding author: HU Guo-Dong, E-mail: xzszhgd@163.com
WANG Ji-Hua, E-mail: jhw25336@126.com
Received: June 11, 2017 Accepted: July 27, 2017
Abstract: The spread of HIV-1 in the world is a serious threat to people's physical and mental health. Residue mutation of HIV-1 protease seriously weakened the effect of drug treatment. In order to study the effects of mutations D30N, I54M and V82A on the interaction between protease and the inhibitor GRL-0519, we carried out four 30 ns molecular dynamics (MD) simulations combined with the solvated interaction energy (SIE) method to calculate the binding free energies of protease and inhibitor. The results show that polar interactions are unfavorable for the mutated protease bonding to the inhibitor, and slightly favorable for WT, the polar interactions are the main driven force for the drug resistance. The calculated total free energies are consistent with the experimental data. In order to show the contribution of each residue to drug resistance, the van der Walls energies of each residue were calculated by the molecular force field method, the hydrogen bonds between inhibitor and protease were also analyzed. The van der Walls analysis implies that the V82A has smaller influence on the binding model. There are five residues with van der Waals contribution larger than 0.4 kcal/mol for D30N, and six residues for I54M. The hydrogen bond analysis suggests that D30N and I54M lost several hydrogen bonds relative to in WT. The result was in accordance with the SIE results. Our study provides theoretical guidance for the design of new and more potent inhibitors against HIV-1 protease variants.
Key words: HIV-1 protease     inhibitor     MD simulation     binding free energy    

Ⅰ型人类免疫缺陷病毒(human immunodeficiency virus typeⅠ,HIV-1) 是艾滋病(acquiredimmune deficiency syndrome,AIDS)的病源[1].HIV在世界范围内的传播,严重地威胁到人们的身心健康.HIV-1蛋白酶对病毒周期正常运转和病毒毒粒成熟至关重要,是病毒复制必需的酶,是抗HIV-1病毒药物的重要靶点,因此抑制HIV-1蛋白酶催化机能的发挥就能阻止HIV-1病毒的复制[2].许多抗HIV的药物就是通过与蛋白酶相互作用发挥药效的,然而实际研究中经常发现蛋白酶的残基变异,这限制了抗病毒药物药效的发挥[3].

HIV-1蛋白酶是由含99个氨基酸的多肽链形成的C2对称的同质二聚体(图 1a),位于二聚体界面上的天冬氨酸残基(Asp25/Asp25')参与催化分解形成了蛋白酶的活性中心,开口处的柔性区域由45~55和45'~55'残基组成.在蛋白酶残基Ile50/Ile50'和抑制剂之间存在一个结晶水分子,此水分子与蛋白酶和抑制剂分别形成2个稳定的氢键[4].在蛋白酶和抑制剂的作用中,经常发现D30N、I54M和V82A残基的变异[5],这3个变异在蛋白酶中的位置如图 1a所示.分析晶体结构发现,D30N可以和抑制剂间形成氢键[6],I54M残基变异可以改变结合区域的构象,V82A残基变异位于活位点[7].当前,GRL-0519抑制剂以其较高的亲和性受到了研究者的关注,其分子结构如图 1b所示[5].虽然,GRL-0519抑制剂与野生型的蛋白酶具有较强的亲和力,但是蛋白酶残基的变异降低了它们的亲和力[8].因此研究HIV-1蛋白酶及其变异与小分子GRL-0519的相互作用显得尤为重要.

Fig. 1 The locations of the three mutations in WT (a) and molecular structure of HIV-protease inhibitor GRL-0519 (b) The protease is displayed in a new cartoon representation, colored by the second structure, GRL-0519 is displayed in a ball and stick representation, and the mutated residues are displayed in a ball with different colors as well as the labeled marks.

分子动力学(MD)模拟已经成为研究生物大分子及大分子与小分子间相互作用的重要工具[9-11],该方法不仅能给出生物大分子在原子水平上的运动细节,而且能够在原子层次上理解和解释实验数据.MD模拟给出的生物大分子的动力学和结构特征是重要的研究依据,然而,与生物过程和药物设计更为密切的是蛋白质小分子的结合自由能[12].人们提出了多种自由能的计算方法[13-15],如:热力学积分(thermodynamic integration,TI)[16-18]、MM-PBSA[19-22]和溶解相互自由能(solvated interaction energy,SIE)[23-25]等方法,TI方法是较为严格的计算方法,但其计算资源消耗较多,SIE方法实现了计算精度和计算资源消耗的合理折中[26].

在本研究中,主要采用MD模拟的方法研究了3个蛋白酶残基变异(D30N、I54M和V82A)对野生型蛋白酶(WT)结合小分子GRL-0519的影响.在MD模拟轨迹的基础上,采用SIE方法计算了小分子和蛋白酶的结合自由能,采用分子力场方法计算了每个残基和小分子的范德华作用能,进而分析了小分子形成的氢键,最终得出变异抗药性的分子机制.

1 材料与方法 1.1 系统搭建

4个复合物的原子坐标取自蛋白质数据库(PDB),WT、D30N、I54M和V82A的PDB代码分别是3OK9、4HDB、4HE9和4HDF[5].在蛋白酶和抑制剂之间,一个水分子起到了重要的桥接作用,这个水分子几乎在所有蛋白酶和抑制剂的复合物中都有发现[27-28].因此在最初的模型中,保留了复合物周围5Å之内的结晶水分子.为了保持2个天冬氨酸残基与抑制剂的羟基之间形成氢键的稳定性,与其他的工作一致,在Asp25的OD2原子上添加了1个质子[29-30].氨基酸的参数取自Amber的FF12SB[31]力场.小分子的力场参数先用Gaussian 03[32]在HF/6-31G*水平上计算小分子的静电势,再用RESP[33]程序拟合小分子各原子的电荷,最后采用GAFF[34]力场参数和拟合电荷在Antechamber程序中得到小分子的力场参数.采用TIP3P[35]水模型构建截去顶角的八面体的水盒子溶解蛋白和小分子,溶质到盒子边缘的最小距离是10Å,同时为了中和系统电性,添加了合适数目的氯离子.

1.2 分子动力学模拟

分子动力学模拟采用Amber12软件包[36]来完成.模拟中采用SHAKE[37]算法限制所含氢原子键的伸缩,模拟步长是2 fs,应用PME[38]方法来计算长程的静电相互作用,且使用了周期性边界条件,非键相互作用的截距(cutoff)为12Å.为了消除最初系统原子间不合理的接触,对4个模拟体系进行了两步能量最小化,首先是最陡下降法,然后是共轭梯度法.能量最小化之后,采用2 kcal/(mol·Å2)的限制常数限制溶质的运动,并在70 ps的模拟时间内把系统从0 K加热到300 K,随后是90 ps的动力学平衡,最后是30 ns的没有限制的常规MD模拟.模拟过程中采用朗之万恒温器限制温度在300 K,压力是一个大气压.采用AmberTools的Ptraj模块解析了蛋白酶主链原子相对于最初构象的均方根偏差(RMSD)、主链原子的均方根波动(RMSF)、氢键等动力学参数.

1.3 SIE方法

SIE方法结合MD模拟的轨迹,可以快速地预测蛋白质和抑制剂的结合自由能[39].在本研究中,从MD模拟轨迹的最后20 ns以50 ps为时间间隔取出了400个构象用于SIE的计算.计算结合自由能的方程如下:

其中EcEvdw分别表示气相中采用分子力场计算的静电相互作用和范德华相互作用,本计算中采用的力场参数和MD模拟的参数一致.ΔGR是抑制剂结合导致的反应场能的变化,使用BRI BEM方法[40]和溶剂探针半径求解泊松方程得到[41].γ·ΔMSA对应于抑制剂结合诱导的溶剂可及表面积的变化.参数α是与熵变相关的比例系数,Din是溶质内部的介电常数,γ是溶剂可及表面积系数,ρ是线性标度的范德华半径系数,C是一个能量常数.在当前计算中,α=0.1048,Din=2.25,ρ=1.1,γ=0.0129 kcal/(mol·Å2),C=-2.89 kcal/mol.SIE计算采用的是Sietraj程序[42].

2 结果与讨论 2.1 MD模拟系统的动力学特征

为了评价30 ns的MD模拟的平衡状态,检测了MD模拟过程中系统的结构变化和能量变化等参数.蛋白酶主链原子的RMSD能够反应MD模拟的稳定性,图 2显示了4个系统的RMSD随模拟时间的变化情况.从第4 ns开始,所有的模拟系统达到了平衡状态,计算了最后20 ns模拟RMSD的平均值,对于WT、D30N、I54M和V82A体系,平均值分别是0.94Å、0.98Å、0.95Å和1.04Å.在4个模拟系统中,WT系统的平均值是最小的,这表明未变异的系统最稳定.随后的解析和自由能计算都是基于平衡后最后20 ns的MD模拟轨迹.

Fig. 2 Root-mean-square deviations (RMSD) of the backbone atoms in MD simulations as a function of MD simulation time
2.2 残基柔性的涨落

主链Cα原子的均方根涨落(RMSF)能够用于评价蛋白酶结构的柔性.图 3a显示了每个复合物中各个残基Cα原子的RMSF.柔性较大的区域是残基16~19/16'~19',35~42/35'~42',52~54/ 52'~54',66~69/66'~69'和78~81/78'~81'.对于所有的复合物,Asp25/Asp25'所在区域的刚性较强,这与接触反应点的特点有关,该结果与其他的相关研究一致[21].在D30N变异中,残基52~54/ 52'~54'表现出较大的灵活性.

Fig. 3 The root mean square fluctuations(RMSFs)and the principal component analysis (PCA)for the four systems (a) The root mean square fluctuations (RMSFs) of Cα atoms versus residue number. (b) Comparison of the eigenvalues plotted against the corresponding eigenvector indices obtained from the Cα covariance matrix conducted from the equilibrium phase of MD simulations.

另外,对MD模拟轨迹最后20 ns共2 000个结构进行了主成分解析.图 3b显示了对角化后的原子波动的协方差矩阵的本征值,相对于对应的本征矢量以一个下降的顺序.最初的5个主成分占49.45% (WT)、57.11% (D30N)、53.27% (I54M)和50.34% (V82A).最初的几个本征值在大小上下降迅速,很快到达了一个收敛的值,这说明系统的主要构象变化是局部变化,残基变异没有引起系统整体上的构象变化.

2.3 结合自由能分析

我们采用SIE方法计算了GRL-0519与HIV-1蛋白酶野生型以及3个残基变异的结合自由能,相应的结合自由能和各个能量项如表 1所示.由表中数据可以看出,虽然计算的结果稍小于实验的结合自由能,但其大小顺序完全一致.在所有的能量项中,ΔEvdw,ΔEcγ·ΔMSA有利于抑制剂和蛋白酶结合,而ΔGR削弱了抑制剂和HIV-1蛋白酶的结合,在考虑了熵的影响之后,结合强度变弱.其中ΔEvdwγ·ΔMSA是非极性相互作用,ΔEc和ΔGR是极性相互作用.综合极性相互作用的两项可以发现:极性相互作用不利于变异的HIV-1蛋白酶结合抑制剂,而轻微有利于WT结合抑制剂.对比WT与变异的各个能量项可以发现:变异对γ·ΔMSA的影响较小;ΔEvdw在I54M中得到加强,而在D30N中减弱.因此,变异导致的药效降低主要是极性相互作用导致的结果.

Table 1 Binding free energies and energy components calculated by SIE method
2.4 范德华作用分析

为了从原子层次上分析变异对结合模式的影响,采用公式(2) 计算了小分子和单个残基的范德华作用能.这样的方法研究蛋白质和小分子的相互作用已经应用到其他的研究工作[25, 44].

公式中的参数AijBij取自Amber的FF12SB力场,R是2个原子ij的距离.共有15个残基的范德华作用能大于1.0 kcal/mol.图 4显示了范德华作用能较大的15个残基在WT系统中的位置及其能量大小.从图 4中可以看出,范德华作用较强的残基主要是和小分子的2个基团(基团一:methoxyphenyl和基团二:(3R、3aS、3bR、6aS、7aS)-octahydrodifuro[2, 3-b:3', 2'-d]furan)相互作用.从和这2个基团相互作用残基的范德华自由能的强度来看,基团二更有利于小分子和蛋白质的范德华作用.

Fig. 4 The position of residues with van de Waals energies larger than 1.0 kcal/mol The inhibitor GRL-0519 is shown in stick and ball representation. The key residues are shown in stick representation. The van der Waals energies of residues are labeled with blue color with unit kcal/mol.

为了分析3个残基变异对HIV-1蛋白酶结合小分子的影响,我们计算了变异复合物中每个残基的范德华贡献相对于未变异复合物贡献的差异,如图 5所示.通过对比发现,V82A变异导致的范德华作用的变化小于其他两个变异,且没有发现能量差大于0.4 kcal/mol的残基,而在D30N中有5个残基(Asp25、Gly27、Ile50、Asp25'和Gly27')差异较大,在I54M变异中有6个残基(Asp25、Gly27、Asp29、Arg8'、Asp25'和Gly27')的差异较大.

Fig. 5 Difference of each residue of the van der Waals energy in mutated complex relative to that in WT complex
2.5 氢键分析

为了进一步研究3个变异残基对HIV-1蛋白酶结合GRL-0519的影响,我们计算了小分子、蛋白酶和桥接水分子的氢键,计算结果如表 2图 6a所示.结果表明,4个复合物中均发现了水分子和蛋白质以及小分子形成的4个氢键.虽然这4个氢键的强度有所不同,但是变异并未导致水分子的桥连作用发生明显的变化.从整体上来看,D30N和I54M变异对氢键的影响大于V82A变异对氢键的影响;Asp25和Asp25'在WT和V82A变异中的差异不大,但是在D30N中小分子与Asp25形成的氢键只有38.10%的占有率,在I54M中只有1个稳定的氢键(图 6b);D30N和I54M中,小分子和基团一没有形成氢键,与基团二形成的氢键也比WT系统中分别少1个(D30N)和2个(I54M).氢键的分析结果表明,D30N和I54M系统的静电作用能小于WT和V82A系统的静电作用能,其结果与SIE的计算一致.

Table 2 Main hydrogen bonds involved in GRL-0519 binding pocket
Fig. 6 The hydrogen bonds formed among the inhibitor GRL-0519, water molecule and the protease (a) All the hydrogen bonds in WT complexes. GRL-0519 is shown in stick and ball representation. The key residues are shown in stick representation. The hydrogen bonds are shown in dash lines. (b) The superimposition of binding pocket of WT and D30N. The GRL-0519 and key residues in WT are shown in stick and ball representation, as well as stick representation in D30N. The hydrogen bonds are in orange dash lines in WT and blue dash lines in D30N.
3 结论

为了研究D30N、I54M和V82A 3个变异对HIV-1蛋白酶的野生型和GRL-0519复合物动力学的影响,本文采用MD模拟的方法对4个系统分别进行了30 ns的模拟.对MD模拟轨迹的分析表明,变异并没有显著改变蛋白酶的整体结构.采用SIE的方法计算了4个系统的结合自由能,计算结果和实验数据一致.分解总的结合自由能到不同的能量项表明,造成变异亲和性降低的主要能量项是极性相互作用;进一步采用分子力场方法计算了单个残基在总结合自由能中的范德华贡献,计算结果表明D30N和I54M变异造成各个残基的范德华作用与未变异的差异较大.最后,对氢键分析表明,WT系统中形成的氢键与V82A变异的差异较小,而与D30N和I54M变异的差异较大.

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中国科学院生物物理研究所和中国生物物理学会共同主办
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文章信息

李高峰, 扈国栋, 张晨, 季保华, 王吉华
LI Gao-Feng, HU Guo-Dong, ZHANG Chen1, JI Bao-Hua1, WANG Ji-Hua
计算方法研究HIV-1蛋白酶及其变异与小分子GRL-0519的相互作用
Study The Interaction Between The HIV-1 Protease and Its Mutations With Inhibitor GRL-0519 by The Computational Method
生物化学与生物物理进展, 2017, 44(9): 783-791
Progress in Biochemistry and Biophysics, 2017, 44(9): 783-791
http://dx.doi.org/10.16476/j.pibb.2017.0053

文章历史

收稿日期: 2017-06-11
接受日期: 2017-07-27

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