Citation: XU Xiejun, XIAO Xingqing, XU Shouhong, LIU Honglai. Computational Study of Thermosensitivity of Liposomes Modulated by Leucine Zipper-Structured Lipopeptides[J]. Acta Physico-Chimica Sinica, ;2019, 35(6): 598-606. doi: 10.3866/PKU.WHXB201806034 shu

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

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

Corresponding author: XIAO Xingqing, xxiao3@ncsu.edu LIU Honglai, hlliu@ecust.edu.cn
Received Date: 19 June 2018
Revised Date: 11 July 2018
Accepted Date: 11 July 2018
Available Online: 7 June 2018
Fund Project: the National Natural Science Foundation of China 21776071the National Natural Science Foundation of China for Innovative Research Groups 51621002the 111 Project of China B08021The project was supported by the National Natural Science Foundation of China (21776071), the National Natural Science Foundation of China for Innovative Research Groups (51621002) and the 111 Project of China (B08021)

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.
- Leucine zipper-structured lipopeptides,
- Thermosensitive liposomes,
- Cancer therapy,
- Drug carrier,
- Molecular dynamics simulation
1. [1]
  Aschenbrenner, D. S. Am. J. Nurs. 2017, 117, 22. doi: 10.1097/01.NAJ.0000521967.00600.3a doi: 10.1097/01.NAJ.0000521967.00600.3a
2. [2]
  Liehr, T. Eur. J. Hum. Genet. 2017, 25, 902. doi: 10.1038/ejhg.2017.7 doi: 10.1038/ejhg.2017.7
3. [3]
  Lokerse, J. M.; Eggermont, M. M.; Grüll, H.; Koning, G. A. J. Controll. Release 2018, 270, 282. doi: 10.1016/j.jconrel.2017.12.012 doi: 10.1016/j.jconrel.2017.12.012
4. [4]
  Mura, P.; Matascia, N.; Nativi, C.; Richichi, B. Eur. J. Pharm. Biopharm. 2018, 122, 54. doi: 10.1016/j.ejpb.2017.10.008 doi: 10.1016/j.ejpb.2017.10.008
5. [5]
  Malaescu, I.; Fannin, P. C.; Marin, C. N.; Lazic, D. Med. Hypotheses 2018, 110, 76. doi: 10.1016/j.mehy.2017.11.004 doi: 10.1016/j.mehy.2017.11.004
6. [6]
  Al-Ahmady, Z. S.; Al-Jamal, W. T.; Bossche, J. V.; Bui, T. T.; Drake, A. F.; Mason, A. J.; Kostarelos, K. ACS Nano 2012, 6, 9335. doi: 10.1021/nn302148p doi: 10.1021/nn302148p
7. [7]
  Srinivasan, M.; Lahiri, D. K. Mol. Neurobiol. 2017, 54, 8063. doi: 10.1007/s12035-016-0277-5 doi: 10.1007/s12035-016-0277-5
8. [8]
  Roodbarkelari, F.; Groot, E. P. New Phytol. 2017, 213, 95. doi: 10.1111/nph.14132 doi: 10.1111/nph.14132
9. [9]
  Wang, S. J.; Shen, Y. X.; Zhang, J. Q.; Xu, S. H.; Liu, H. L. Phys. Chem. Chem. Phys. 2016, 18, 10129. doi: 10.1039/C6CP00378H doi: 10.1039/C6CP00378H
10. [10]
  Wang, S. J.; Han, X.; Liu, D. Y.; Li, M. Y.; Xu, S. H.; Liu, H. L. Langmuir 2017, 33, 1478. doi: 10.1021/acs.langmuir.6b04080 doi: 10.1021/acs.langmuir.6b04080
11. [11]
  Wang, S. J.; Li, M. Y.; Xu, S. H.; Liu, H. L. Acta Phys. -Chim. Sin. 2017, 33, 829. doi: 10.3866/PKU.WHXB201701062
12. [12]
  Xu, X. X.; Xiao, X. Q.; Xu, S. H.; Liu, H. L. Phys. Chem. Chem. Phys. 2016, 18, 25465. doi: 10.1039/C6CP05145F doi: 10.1039/C6CP05145F
13. [13]
  Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Kollmann, P. A. J. Am. Chem. Soc. 1993, 115, 9620. doi: 10.1021/ja00074a030 doi: 10.1021/ja00074a030
14. [14]
  Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W.; Kollman, P. A. J. Am. Chem. Soc. 1995, 117, 5179. doi: 10.1021/ja00124a002 doi: 10.1021/ja00124a002
15. [15]
  Cieplak, P.; Cornell, W. D.; Bayly, C. I.; Kollmann, P. A. J. Comput. Chem. 1995, 16, 1357. doi: 10.1002/jcc.540161106 doi: 10.1002/jcc.540161106
16. [16]
  Abraham, M. J.; Murtola, T.; Schulz, R.; Pll, S.; Smith, J. C.; Hess, B.; Lindahl, E. SoftwareX 2015, 1–2, 19. doi: 10.1016/j.softx.2015.06.001 doi: 10.1016/j.softx.2015.06.001
17. [17]
  Pronk, S.; Pall, S.; Schulz, R.; Larsson, P.; Bjelkmar, P.; Apostolov, R.; Shirts, M. R.; Smith, J. C.; Kasson, P. M.; van der Spoel, D.; et al. Bioinformatics 2013, 29, 845. doi: 10.1093/bioinformatics/btt055 doi: 10.1093/bioinformatics/btt055
18. [18]
  Maier, J.; Martinez, C.; Kasavajhala, K.; Wickstrom, L.; Hauser, K.; Simmerling, C. J. Chem. Theory Comput. 2015, 11, 3696. doi: 10.1021/acs.jctc.5b00255 doi: 10.1021/acs.jctc.5b00255
19. [19]
  Onufriev, A.; Bashford, D.; Case, D. A. Proteins: Struct., Funct., Bioinf. 2004, 55, 383. doi: 10.1002/prot.20033 doi: 10.1002/prot.20033
20. [20]
  Martínez, L.; Andrade, R.; Birgin, E. G.; Martínez, J. M. J. Comput. Chem. 2009, 30, 2157. doi: 10.1002/jcc.21224 doi: 10.1002/jcc.21224
21. [21]
  Martínez, J. M.; Martínez, L. J. Comput. Chem. 2003, 24, 819. doi: 10.1002/jcc.10216 doi: 10.1002/jcc.10216
22. [22]
  Biasini, M.; Bienert, S.; Waterhouse, A.; Arnold, K.; Studer, G.; Schmidt, T.; Kiefer, F.; Cassarino, T. G.; Bertoni, M.; Bordoli, L.; et al. Nucleic Acids Res. 2014, 42, 252. doi: 10.1093/nar/gku340 doi: 10.1093/nar/gku340
23. [23]
  Kiefer, F.; Arnold, K.; Künzli, M.; Bordoli, L.; Schwede, T. Nucleic Acids Res. 2009, 37, 387. doi: 10.1093/nar/gkn750 doi: 10.1093/nar/gkn750
24. [24]
  Arnold, K.; Bordoli, L.; Kopp, J.; Schwede, T. Bioinformatics 2006, 22, 195. doi: 10.1093/bioinformatics/bti770 doi: 10.1093/bioinformatics/bti770
25. [25]
  Dickson, C. J.; Madej, B. D.; Skjevik, A. A.; Betz, R. M.; Teigen, K.; Gould, I. R.; Walker, R. C. J. Chem. Theory Comput. 2014, 10, 865. doi: 10.1021/ct4010307 doi: 10.1021/ct4010307
26. [26]
  Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. J. Chem. Phys. 1983, 79, 926. doi: 10.1063/1.445869 doi: 10.1063/1.445869
27. [27]
  Altis, A.; Nguyen, P. H.; Hegger, R.; Stock, G. J. Chem. Phys. 2007, 126, 244111. doi: 10.1063/1.2746330 doi: 10.1063/1.2746330
28. [28]
  Borgohain, G.; Paul, S. Mol. Simul. 2017, 43, 52. doi: 10.1080/08927022.2016.1233546 doi: 10.1080/08927022.2016.1233546
29. [29]
  Kabsch, W.; Sander, C. Biopolymers 1983, 22, 2577. doi: 10.1002/bip.360221211 doi: 10.1002/bip.360221211
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