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物理化学学报  2019, Vol. 35 Issue (6): 598-606    DOI: 10.3866/PKU.WHXB201806034
论文     
亮氨酸拉链型脂肽对脂质体温敏性调节的分子模拟
许谢君1,肖兴庆2,*(),徐首红1,刘洪来1,*()
1 华东理工大学化学与分子工程学院,化学工程国家重点实验室,上海 200237
2 Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA
Computational Study of Thermosensitivity of Liposomes Modulated by Leucine Zipper-Structured Lipopeptides
Xiejun XU1,Xingqing XIAO2,*(),Shouhong XU1,Honglai LIU1,*()
1 State Key Laboratory of Chemical Engineering, College of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China
2 Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA
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摘要:

含亮氨酸拉链型脂肽的温敏性脂质体被认为是抗癌药物的优良载体。亮氨酸拉链型脂肽的主要氨基酸残基序列为[VAQLEVK-VAQLESK-VSKLESK-VSSLESK],嵌入脂质体后可以有效改善脂质体的温敏性。本文首先采用隐式溶剂副本交换分子动力学方法,对N端修饰的亮氨酸拉链单链的折叠状态进行了模拟,得到了亮氨酸拉链单链的转变温度。并对包含该种新型亮氨酸拉链型脂肽的DPPC脂质体进行常规分子动力学模拟,研究了2种不同头基的亮氨酸拉链型脂肽(ALA,C3CO)二聚体嵌入后DPPC脂质体的相转变温度变化,证明了亮氨酸拉链型脂肽对于该脂质体温敏性的控制作用。利用这一规律,可以对亮氨酸拉链型脂肽进行优化改良,得到效果更佳的温敏脂质体,对于抗癌药物载体的开发有着重要的意义。

关键词: 亮氨酸拉链温敏脂质体癌症治疗药物载体分子动力学模拟    
Abstract:

Leucine zipper-functionalized liposomes are promising drug carriers for cancer treatment because of their unique thermosensitivity. The leucine zippers, which consist of two α-helical polypeptides that dimerize in parallel, have characteristic heptad repeats (represented by [abcdefg]n). A leucine residue was observed periodically at site "d" to stabilize the dimerization of the two polypeptides through inter-chain hydrophobic interactions. As the temperature increased, the inter-chain hydrophobic interactions became weaker, eventually triggering the dissociation of the leucine zippers. Due to the unique nature of the temperature response, leucine zippers are useful for developing novel lipid-peptide vesicles for drug delivery because they allow for better control and optimization of drug release under mild hyperthermia. The base sequence of the leucine zipper peptides used in our lab for the functionalize liposomal carrier is [VAQLEVK-VAQLESK-VSKLESK-VSSLESK]. Our recent experiments revealed that modifying this peptide at the N-terminus with distinct functional groups can change the physicochemical properties of the lipopeptides, and eventually affect the liposomes' phase transition behaviors. Four leucine zipper-structured lipopeptides with distinct head groups, viz. ALA, C3CO, C5CO, and POCH, were studied computationally to examine the influence of the molecular structures on the phase transition behaviors of lipopeptides. A series of computational techniques including quantum mechanics (QM) calculations, implicit solvation replica exchange molecular dynamics (REMD) simulations, dihedral principal component analysis (dPCA), and dictionary of protein secondary structure (DSSP) methods, and the conventional explicit solvation molecular dynamics (MD) simulations were applied in this work. First, QM calculations were conducted to obtain the partial charges of some modified head groups. Implicit-solvent REMD simulations were then performed to study the effect of temperature on the folded conformations of the leucine zipper peptides. The dPCA method was used to simulate trajectories to identify representative structures of the peptides at various temperatures, and the DSSP method was used to determine conformation transitions of the four lipopeptides ALA, C3CO, C5CO, and POCH at 324.8, 312.1, 319.1, and 319.4 K, respectively. The thermostability of the lipopeptide dimers in the lipid DPPC bilayer was studied in the conventional explicit solvent MD simulations. Finally, we conducted a deep analysis on the area per lipid and the electron-density profile for the DPPC bilayer to explore the folding and unfolding processes of the lipopeptides in the liposomes to better understand the underlying phase transition mechanisms of the thermosensitive liposomes. On this basis, we could further improve the thermosensitivity of the leucine zipper-structured lipopeptides, thereby facilitating the development of liposomal drug delivery techniques in the future.

Key words: Leucine zipper-structured lipopeptides    Thermosensitive liposomes    Cancer therapy    Drug carrier    Molecular dynamics simulation
收稿日期: 2018-06-19 出版日期: 2018-07-16
中图分类号:  O647  
基金资助: 国家自然科学基金(21776071);国家自然科学基金创新群体(51621002);教育部111引智计划(B08021)
通讯作者: 肖兴庆,刘洪来     E-mail: xxiao3@ncsu.edu;hlliu@ecust.edu.cn
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引用本文:

许谢君,肖兴庆,徐首红,刘洪来. 亮氨酸拉链型脂肽对脂质体温敏性调节的分子模拟[J]. 物理化学学报, 2019, 35(6): 598-606, 10.3866/PKU.WHXB201806034

Xiejun XU,Xingqing XIAO,Shouhong XU,Honglai LIU. Computational Study of Thermosensitivity of Liposomes Modulated by Leucine Zipper-Structured Lipopeptides. Acta Phys. -Chim. Sin., 2019, 35(6): 598-606, 10.3866/PKU.WHXB201806034.

链接本文:

http://www.whxb.pku.edu.cn/CN/10.3866/PKU.WHXB201806034        http://www.whxb.pku.edu.cn/CN/Y2019/V35/I6/598

图1  包含亮氨酸拉链型脂肽的温敏性脂质体
图2  亮氨酸拉链型脂肽结构
Lipopeptide Sequence
ALA A-[VAQLEVK-VAQLESK-VSKLESK-VSSLESK]
POCH (CH3)3-N+-(CH2)2-O-P(O)2-O-CH2-[VAQLEVK-VAQLESK-VSKLESK-VSSLESK]
C3CO CH3-(CH2)2-CO-[VAQLEVK-VAQLESK-VSKLESK-VSSLESK]
C5CO CH3-(CH2)4-CO-[VAQLEVK-VAQLESK-VSKLESK-VSSLESK]
表1  亮氨酸拉链型脂肽及其序列
图3  连接着缬氨酸的疏水性基团CH3―(CH2)2―CO―
Index of the atom Atom types Partial charges/e Index of the atom Atom types Partial charges/e
1 c3 0.0665 7 hc ?0.0604
2 hc 0.0102 8 c3 ?1.9082
3 hc 0.0102 9 hc 0.4705
4 hc 0.0102 10 hc 0.4705
5 c3 0.4968 11 c 2.0105
6 hc ?0.0604 12 o ?0.5164
表2  疏水性基团CH3―(CH2)2―CO―的电荷
图4  含有亮氨酸拉链结构的DPPC双分子层的初始结构
图5  亮氨酸拉链的势能概率分布图((a) C3CO,(b) POCH)以及亮氨酸拉链在325 K副本下副本交换图((c) C3CO,(d) POCH)
图6  (a,b) 285 K,(c,d) 325 K以及(e,f) 380 K温度下,C3CO、POCH脂肽的自由能面图($φ$)
图7  温度对于(a) C3CO,(b) POCH脂肽的α螺旋结构的影响
图8  脂肽二聚体在50 ns分子模拟中在310,315,320以及325 K的RMSD曲线
图9  310,315,320和325 K时DPPC脂质体的脂分子面积以及电子密度随温度的变化曲线
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