Structural stability of insulin in imidazolium ionic liquids by molecular simulation

doi:10.11949/j.issn.0438-1157.20160968

Abstract

Abstract:

Ionic liquids, as a kind of novel green solvents, have been widely applied to structural stability study of protein due to their unique physicochemical properties. In this study, insulin was chosen as a heat-sensitive protein medicine to research the structural stability of protein in various imidazolium ionic liquids from a molecular insight by using molecular dynamics simulation. The results indicate that the ionic liquids are able to stabilize the molecular structure of insulin effectively at room temperature compared with aqueous solution. The RMSD values and the secondary structure of insulin show that the weaker the hydrogen-bond basicity of anion is, the shorter the alkyl chain of cation is, the more stable the molecular structure of insulin is. In order to explain thoroughly the effect of alkyl chain length of ionic liquid on the stability of the protein, the interaction and the number of contact between the insulin and dicyanamide imidazolium ionic liquids with different alkyl chain length are further analyzed. It is found that the cation stabilize effectively the molecular structure of insulin which relies mainly on the electrostatic interaction between the insulin and the 1-methylimidazole of cation. Comparing to ionic liquids with long alkyl chain, the interaction between the insulin and ionic liquids is more powerful, and the insulin also adsorb more anion and 1-methylimidazole of cation in ionic liquids with short alkyl chain. All these results indicate that the ionic liquids with short chain alkyl indeed improve the molecular structural stability of insulin. Generally, the molecular dynamic simulation, as adopted to this research, provides a molecular insight to investigate the stability of insulin in ionic liquids, which is important and essential for molecular design of ionic liquids and stability study of heat-sensitive protein drugs.

Key words: ionic liquids, insulin, protein stability, interaction energy, molecular simulation

摘要：

离子液体作为一种新型绿色溶剂，由于其独特的物理化学性质，被广泛应用于蛋白质的稳定性研究。选用热敏性蛋白药物胰岛素作为研究对象，采用分子动力学模拟方法，从分子层面上研究不同种类的离子液体对胰岛素结构的稳定效果。结果表明，与纯水体系相比，在常温下离子液体能够有效地稳定胰岛素的分子结构，且体系中阴离子的氢键碱性越弱，阳离子的烷基链越短，对胰岛素分子结构的稳定作用越强。并深入分析不同烷基链长度的二氰胺类离子液体与胰岛素之间的相互作用，发现相较于长烷基链离子液体，短烷基链离子液体与胰岛素之间的相互作用更强，揭示了后者能更好地维持和稳定胰岛蛋白的分子结构。

关键词: 离子液体, 胰岛素, 蛋白质稳定性, 相互作用能, 分子模拟

CLC Number:

O6-39

PAN Xiaoli, LI Daixi, WEI Dongqing. Structural stability of insulin in imidazolium ionic liquids by molecular simulation[J]. CIESC Journal, 2016, 67(12): 5215-5221.

潘晓莉, 李代禧, 魏冬青. 离子液体中胰岛素结构稳定性的分子动力学模拟[J]. 化工学报, 2016, 67(12): 5215-5221.

References 32

[1]	王宇新, 周晓巍, 党颖, 等. 提高蛋白质和多肽类药物代谢稳定性的研究进展[J]. 生物技术通讯, 2005, 16(6):665-667. WANG Y X, ZHOU X W, DANG Y, et al. Progress in the stability of protein and polypeptide drugs[J]. Letters in Biotechnology, 2005, 16(6):665-667.
[2]	任勇, 丁东平, 渠刚, 等. 蛋白质类药物的稳定性研究进展[J]. 华南国防医学杂志, 2006, 20(4):31-33. REN Y, DING D P, QU G, et al. Advances stability of the protein drugs[J]. Military Medical Journal of South China, 2006, 20(4):31-33.
[3]	RICHTER B, NEISES G. ‘Human’ insulin versus animal insulin in people with diabetes mellitus[J]. Cochrane Database Syst. Rev., 2002, 3(3):CD003816.
[4]	李代禧, 张燕, 郭柏松, 等. 低温干燥过程中LEA蛋白对胰岛素结构稳定性的研究[J]. 生物医学工程学杂志, 2013, 30(4):854-859. LI D X, ZHANG Y, GUO B S, et al. Investigation on bioactive protection of LEA protein for insulin by molecular simulation in the low-temperature drying process[J]. Biomed. Eng., 2013, 30(4):854-859.
[5]	RAJAN P, MEENA K, ABBUL B K. Recent advances in the applications of ionic liquids in protein stability and activity:a review[J]. Appl. Biochem. Biotechnol., 2014, 172(8):3701-3720.
[6]	NAUSHAD M, ALOTHMAN Z A, KHAN A B, et al. Effect of ionic liquid on activity, stability, and structure of enzymes:a review[J]. Int. J. Biol. Macromol., 2012, 51(4):555-560.
[7]	KAAR J L, JESIONOWSKI A M, BERBERICH J A, et al. Impact of ionic liquid physical properties on lipase activity and stability[J]. J. Am. Chem. Soc., 2003, 125(14):4125-4131.
[8]	HERNANDEZ-FERNANDEZ F J, DELOSRIOS A P, TOMAS-ALONSO F, et al. Stability of hydrolase enzymes in ionic liquids[J]. Canadian J. Chem. Eng., 2009, 87(6):910-914.
[9]	YANG Z, YUE Y J, HUANG W C. Importance of the ionic nature of ionic liquids in affecting enzyme performance[J]. J. Biochem., 2009, 145(3):355-364.
[10]	YASAR A, MATTHIAS J N J, DARIUSH H. Effect of ionic liquids on the solution structure of human serum albumin[J]. Biomacromolecules, 2011, 12(4):1072-1079.
[11]	娄文勇, 宗敏华.离子液体的组成及溶剂性质与木瓜蛋白酶催化特性的关系[J]. 高等学校化学学报, 2007, 28(7):1283-1287. LOU W Y, ZONG M H. Correlation between catalytic characteristics of papain and components and solvate properties of ionic liquids[J]. Chem. J. Chinese Universities, 2007, 28(7):1283-1287.
[12]	YAO P, YU X, HUANG X. Effect of the physicochemical properties of binary ionic liquids on lipase activity and stability[J]. Int. J. Biol. Macromol., 2015, 77:243-249.
[13]	KRUGER P, STRBBURGER W, WOLLMER A, et al. The simulated dynamic of the insulin monomer and their relationship to the molecule's structure[J]. Eur. Biophys. J., 1987, 14:449-459.
[14]	吴云剑, 崔颖璐, 郑清川, 等. CYP2C9酶与Warfarin结合模型的立体选择性理论研究[J]. 高等学校化学学报, 2014, 35(12):2605-2611. WU Y J, CUI Y L, ZHENG Q C, et al. Theoretical studies on the substrate binding mode and regioselectivity of human CYP2C9 with S-and R-warfarin[J]. Chem. J. Chinese Universities, 2014, 35(12):2605-2611.
[15]	NAGAMPALLI R S, KRISHNA, VASANTHA, et al. Metal induced conformational changes in human insulin:crystal structure of Sr2+, Ni2+ and Cu2+ complexes of human insulin[J]. Protein Pept. Lett., 2011, 18(5):457-466.
[16]	VAN DER S D, LINDAHL E. GROMACS:fast, flexible and free[J]. J. Comput. Chem., 2005, 26(16):1701-1718.
[17]	VYTATUAS G, SERVAAS M, DANIEL S. Automated protein structure and topology generation for alchemical perturbations[J]. J. Comput. Chem., 2015, 36(5):348-354.
[18]	ALEXEI M N, YURY V M, ALEXANDER P L. A new AMBER-compatible force field parameter set for alkanes[J]. J. Mol. Model., 2014, 20(3):1-10.
[19]	PEIKUN Y. Incroporation of the TIP4P water model into a continuum solvate for computing salvation free energy[J]. Chem. Phys., 2014, 443:93-106.
[20]	WANG H, DOMMERT F, HOLM C. Optimizing working parameters of the smooth particle mesh Ewald algorithm in terms of accuracy and efficiency[J]. Chem. Phys., 2010, 133(3):034117-034128.
[21]	ANIRBAN M, CHARUSITA C. Effect of the Berendsen thermostat on the dynamical properties of water[J]. Mol. Phys., 2004, 102(7):681-685.
[22]	BUSSI G, ZYKOVA-TIMAN T, PARRINELLO M. Isothermal-isobaric molecular dynamics using stochastic velocity rescaling[J]. Chem. Phys., 2009, 130(7):074101-074109.
[23]	RENTENIER A, MORETTO-CAPELLE P, BORDENAVE-MONTESQUIEU D, et al. Analysis of fragment size distributions in collision of monocharged ions with the C60 molecule[J]. J. Phys. B:At., Mol. Opt. Phys., 2005, 38(7):789-806.
[24]	RATHORE B, SHAKYA M. Insilico 3D structure prediction of E-cadherin protein:a molecule responsible for suppressing melanoma metastasis[J]. J. Adv. Bioinformatics Applications Res., 2012, 3(2):310-316.
[25]	杨程, 卢滇楠, 张敏莲, 等. 分子动力学模拟二硫键对胰岛素构象稳定性的影响[J]. 化工学报, 2010, 61(4):929-934. YANG C, LU D N, ZHANG M L, et al. Molecular dynamjcs simulation of impact of disulfide bridge on conlbrmational stability of insulin[J]. CIESC Journal, 2010, 61(4):929-934.
[26]	胡小玲, 郭小青, 管萍, 等. 在离子液体中蛋白质溶解性及稳定性的研究进展[J]. 功能材料, 2013, 44(12):1679-1685. HU X L, GUO X Q, GUAN P, et al. Research progress of dissolution and stability of protein in ionic liquids[J]. J. Functional Materials, 2013, 44(12):1679-1685.
[27]	BAHAREH D, SARA D, ABBAS A S, et al. Effect of ionic liquids on the structure, stability and activity of two related α-amylases[J]. Int. J. Biol. Macromol., 2011, 48(1):93-97.
[28]	PHIL C, CLAUS A F A, BURKHARD R, et al. DSSPcont:continuous secondary structure assignments for proteins[J]. Nucleic Acids Res., 2003, 31(13):3293-3295.
[29]	YAN H, WU J Y, DAI G L, et al. Interaction mechanisms of ionic liquids[Cnmim]Br(n 4, 6,8,10) with bovine serum albumin[J]. J. Luminescence, 2012, 132(3):622-628.
[30]	MEI Q Q, HOU M Q, NING H, et al. Microstructure and intermolecular interactions of[Bmim][PF6]+water+alcohol systems:a molecular dynamics simulation study[J]. Acta Phys. -Chim. Sin., 2014, 30(12):2210-2215.
[31]	LIU F F, DONG X Y, WANG T, et al. Rational design of peptide ligand for affinity chromatography of tissue-type plasminogen activator by the combination of docking and molecular dynamics simulations[J]. J. Chromatography A, 2007, 1175:249-258.
[32]	白姝, 常颖, 刘小娟, 等. 海藻糖与氨基酸之间相互作用的分子动力学模拟[J]. 物理化学学报, 2014, 30(7):1239-1246. BAI S, CHANG Y, LIU X J, et al. Interactions between trehalose and amino acids by molecular dynamics simulations[J]. Acta Phys. -Chim. Sin., 2014, 30(7):1239-1246.