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Acta Phys. -Chim. Sin.  2019, Vol. 35 Issue (6): 598-606    DOI: 10.3866/PKU.WHXB201806034
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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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 wordsLeucine zipper-structured lipopeptides      Thermosensitive liposomes      Cancer therapy      Drug carrier      Molecular dynamics simulation     
Received: 19 June 2018      Published: 16 July 2018
MSC2000:  O647  
Fund:  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)
Corresponding Authors: Xingqing XIAO,Honglai LIU     E-mail:;
Cite this article:

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.

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Fig 1 Thermosensitive liposome with leucine zipper-structured lipopeptides.
Fig 2 Leucine zipper-structured lipopeptides. (a) double helix structure of leucine zipper; (b) overhead view of a leucine zipper, where site d is predominantly occupied by the leucine residue.
Lipopeptide Sequence
Table 1 Sequences of leucine zipper-structured lipopeptides.
Fig 3 The hydrophobic group CH3(CH2)2―CO―capped by the valine residue. The total charge of the molecule is +e.
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
Table 2 Partial charges of the hydrophobic group CH3―(CH2)2―CO― in the C5CO peptide
Fig 4 Initial structures of the lipopeptide dimers complexed with lipid DPPC bilayer and water. (a) blank, (b) ALA, (c) C3CO.
Fig 5 The probability distributions of the potential energy of the replicas ((a) C3CO, (b) POCH) and time series of temperature exchanges at 325 K ((c) C3CO, (d) POCH).
Fig 6 Free energy landscape ($φ$) along the first two principal components (V1, V2) for the C3CO lipopeptide at (a) 285 K, (c) 325 K and (e) 380 K, and for the POCH lipopeptide at (b) 285 K, (d) 325 K and (f) 380 K
Fig 7 The effect of temperature on the α-helical conformation of the (a) C3CO and (b) POCH lipopeptides. The least square method is used to determine the temperature-dependence conformation transition. Calculation errors are estimated by the standard errors of the mean.
Fig 8 The RMSD profiles of the lipopeptide dimers in the 50 ns conventional MD simulations at 310, 315, 320 and 325 K. (a) blank, (b) ALA, (c) C3CO.
Fig 9 The area per lipid for DPPC bilayers and electron-density profile for DPPC bilayers at 310, 315, 320 and 325 K. (a, d) blank, (b, e) ALA, (c, f) C3CO.
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