### 亮氨酸拉链型脂肽对脂质体温敏性调节的分子模拟

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
• 收稿日期:2018-06-19 录用日期:2018-07-11 发布日期:2018-10-31
• 通讯作者: 肖兴庆,刘洪来 E-mail:xxiao3@ncsu.edu;hlliu@ecust.edu.cn
• 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)

### Computational Study of Thermosensitivity of Liposomes Modulated by Leucine Zipper-Structured Lipopeptides

Xiejun XU1,Xingqing XIAO2,*(),Shouhong XU1,Honglai LIU1,*()

1. 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
• Received:2018-06-19 Accepted:2018-07-11 Published:2018-10-31
• Contact: Xingqing XIAO,Honglai LIU E-mail:xxiao3@ncsu.edu;hlliu@ecust.edu.cn
• Supported by:
the National Natural Science Foundation of China(21776071);the National Natural Science Foundation of China for Innovative Research Groups(51621002);the 111 Project of China(B08021)

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.

MSC2000:

• O647