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。
Leucine zipper-functionalized liposomes are promising drug carriers for cancer treatment because of their unique thermosensitivity.The leucine zippers,which consist of twoα-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 zipperstructured lipopeptides with distinct head groups,viz.ALA,C3 CO,C5 CO,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(dP CA),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.Implicitsolvent REMD simulations were then performed to study the effect of temperature on the folded conformations of the leucine zipper peptides.The dPCA method was use
作者
许谢君
肖兴庆
徐首红
刘洪来
XU Xiejun;XIAO Xingqing;XU Shouhong;LIU Honglai(State Key Laboratory of Chemical Engineering,College of Chemistry and Molecular Engineering,East China University ofScience and Technology,Shanghai200237,P.R.China;Chemical and Biomolecular Engineering,North Carolina State University,Raleigh,NC27695-7905,USA)
出处
《物理化学学报》
SCIE
CAS
CSCD
北大核心
2019年第6期598-606,共9页
Acta Physico-Chimica Sinica
基金
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)资助项目~~
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
Leucine zipper-structured lipopeptides
Thermosensitive liposomes
Cancer therapy
Drug carrier
Molecular dynamics simulation
