Structural Stability of ADTC5 Peptide: Conformational Insights into Dynamics and Its Binding Mode

Parsaoran Siahaan, Vivitri Dewi Prasasty, Bungaran David Simanjuntak, Suci Hildayani, Khairul Anam


The cyclic structure of ADTC5 (Ac-CDTPPVC-NH2) peptide is known has ability to modulate homo dimer E-cadherin interactions to form adherens junction at the intercellular junction.  The ability to inhibit E-cadherin interaction has become important to increase paracellular porosity in delivering drug molecules to the target cell. There are two types of ADTC5 state: opened-cyclic state (OCS) and closed-cyclic state (CCS). OCS of ADTC5 is affected by distance constraint and CCS is formed by disulfide bond from terminal cysteines through force restraint. The aim of this research is to investigate the inhibition activity of ADTC5 peptide upon E-cadherin. Here we used molecular docking and molecular dynamics approaches. The structure of ADTC5 peptide was generated by PyMOL program. GROMACS v4.5.5 was utilized to simulate molecular dynamics. The optimized ADTC5 molecule was placed in aqueous or polar condition at physiological pH. Furthermore, ADTC5 was docked with EC1-EC2 coupled domain of E-cadherin using AutoDock 4.2 and be refined using molecular dynamic (MD). The result showed that CCS ADTC5 peptide has stronger affinity and more stable interaction with EC1-EC2 coupled domain than the OCS one.


ADTC5 peptide, E-cadherin, Molecular Dynamics, Molecular Docking

Full Text:



Brown RC, Davis TP (2002) Calcium modulation of and tight junction function: a potential mechanism for blood-brain barrier disruption after stroke. Stroke 33: 1706-1711. doi: 10.1161/01.STR.0000016405.06729.83

Majumdar S, Siahaan TJ (2012) Peptide-mediated targeted drug delivery. Medicinal Research Reviews 32 (3): 637-658. doi: 10.1002/med.20225.

Lutz KL, Siahaan TJ (1997) Molecular structure of the apical junction complex and its contribution to the paracellular barrier. Journal of Pharmaceutical Sciences 86: 977-984.

Menard S, Cerf-Bensussan N, Heyman M (2010) Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunology 3 (3): 247-259. doi: 10.1038/mi.2010.5.

N'Da DD (2014) Review prodrug strategies for enhancing the percutaneous absorption of drugs. Molecules 19 (12): 20780-20807. doi: 10.3390/molecules191220780.

Sinaga E, Jois SD, Avery M, Makagiansar IT et al. (2002) Increasing paracellular porosity by E-cadherin peptides: Discovery of bulge and groove regions in the EC1-domain of E-cadherin. Pharmaceutical Research. 19 (8): 1170-1179.

Laksitorini MD, Kiptoo PK, On NH et al. (2015) Modulation of intercellular junctions by cyclic-ADT peptides as a method to reversibly increase blood-brain barrier permeability. Journal of Pharmaceutical Sciences 104 (3): 1065-1075. doi: 10.1002/jps.24309.

Zheng K, Laurence JS, Kuczera K et al. (2009) Characterization of multiple stable conformers of the EC5 domain of E-cadherin and the interaction of EC5 with E-cadherin peptides. Chemical Biology and Drug Design 73 (6): 584-598. doi: 10.1111/j.1747-0285.2009.00818.x.

Kiptoo P, Sinaga E, Calcagno AM et al. (2011) Enhancement of drug absorption through the blood-brain barrier and inhibition of intercellular tight junction resealing by E-cadherin peptides. Molecular Pharmaceutics 8 (1): 239-249. doi: 10.1021/mp100293m

van Holde KE, Johnson WC, Ho PS (2006) Principles of physical biochemistry, Second Edition. New Jersey, Pearson Prentice Hall.

Siahaan P, Radiman CL, Rahayu SI et al. (2007) Investigation of molecular interaction between Phenylacetylene and Hexamethylphosphoric triamide by 13C NMR T1relaxation time studies and Ab initio QM calculations. Indonesian Journal of Chemistry 7 (3):

Klimovich PV, Mobley DL (2015) A Python tool to set up relative free energy calculations in GROMACS. Journal of Computer-Aided Molecular Design. Journal of Computer-Aided Molecular Design 29 (11): 1007-1014. doi: 10.1007/s10822-015-9873-0.

Pronk S, Pall S, Schulz R et al. (2013) GROMACS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29 (7): 845-854. doi: 10.1093/bioinformatics/btt055.

van der Spoel D, van Maaren PJ, Caleman C (2012) GROMACS molecule and liquid database. Bioinformatics 28 (5): 752-753. doi: 10.1093/bioinformatics/bts020.

van der Spoel D, Lindahl E, Hess B et al. (2015)

GROMACS: Fast, flexible, and free. Journal of Computational Chemistry 26 (16): 1701-1718. doi: 10.1002/jcc.20291.

Lindorff-Larsen K, Maragakis P, Piana S et al. (2012) Systematic validation of protein force fields against experimental data. PloS One 8 (4). doi: 10.1371/journal.pone.0032131.

van der Spoel D, Lindahl E, Hess B, the GROMACS development team (2013) GROMACS User manual version 4.6. Accessed: January 2017.

Rentzsch R, Renard BY (2015) Docking small peptides remains a great challenge: An assessment using AutoDock Vina. Briefings in Bioinformatics. 16 (6): 1045-1056. doi: 10.1093/bib/bbv008.

Hill AD, Reilly PJ (2015) Scoring Functions for AutoDock. In: Lutteke T, Frank M (eds) Glycoinformatics. New York, Springer, pp 467–474.

Morris GM, Huey R, Lindstrom W et al. (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry (16): 2785-2791. doi: 10.1002/jcc.21256.

Wang X, Snoeyink J (2006) Multiple structure alignment by optimal RMSD implies that the average structure is a consensus. Computational systems bioinformatics / Life Sciences Society. Computational Systems Bioinformatics Conference 5: 79-87.

Bruschweiler R (2003) Efficient RMSD measures for the comparison of two molecular ensembles. Root-mean-square deviation. Proteins 50 (1): 26-34. doi: 10.1002/prot.10250.

Reva BA, Finkelstein AV, Skolnick J (1998) What is the probability of a chance prediction of a protein structure with an RMSD of 6 A? Folding and Design. 3: 141-147.

Parisini E, Higgins JM, Liu JH et al. (2007) The crystal structure of human E-cadherin domains 1 and 2, and comparison with other cadherins in the context of adhesion mechanism. Journal of Molecular Biology 373 (2): 401-411. doi: 10.1016/j.jmb.2007.08.011.

Tie Y, McPhail B, Hong H et al. (2012) Modeling chemical interaction profiles: II. Molecular docking, spectral data-activity relationship, and structure-activity relationship models for potent and weak inhibitors of cytochrome P450 CYP3A4 isozyme. Molecules 17 (3): 3407-3460. doi: 10.3390/molecules17033407.


Copyright (c) 2017 Journal of Tropical Life Science