title: Probing the interaction between cHAVc3 peptide and the EC1 domain of E-cadherin using NMR and molecular dynamics simulations.
abstract: The goal of this work is to probe the interaction between cyclic cHAVc3 peptide and the EC1 domain of human E-cadherin protein. Cyclic cHAVc3 peptide (cyclo(1,6)Ac-CSHAVC-NH2) binds to the EC1 domain as shown by chemical shift perturbations in the 2D1H,-15N-HSQC NMR spectrum. The molecular dynamics (MD) simulations of the EC1 domain showed folding of the C-terminal tail region into the main head region of the EC1 domain. For cHAVc3 peptide, replica exchange molecular dynamics (REMD) simulations generated five structural clusters of cHAVc3 peptide. Representative structures of cHAVc3 and the EC1 structure from MD simulations were used in molecular docking experiments with NMR constraints to determine the binding site of the peptide on EC1. The results suggest that cHAVc3 binds to EC1 around residues Y36, S37, I38, I53, F77, S78, H79, and I94. The dissociation constants (Kdvalues) of cHAVc3 peptide to EC1 were estimated using the NMR chemical shifts data and the estimated Kds are in the range of .5 × 10-5-7.0 × 10-5M.
authors.affiliation: a Department of Pharmaceutical Chemistry , The University of Kansas , 2095 Constant Avenue, Lawrence , KS 66047 , USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alaofi
authors.affiliation: a Department of Pharmaceutical Chemistry , The University of Kansas , 2095 Constant Avenue, Lawrence , KS 66047 , USA.
authors.forename: Elinaz
authors.initials: E
authors.lastname: Farokhi
authors.affiliation: a Department of Pharmaceutical Chemistry , The University of Kansas , 2095 Constant Avenue, Lawrence , KS 66047 , USA.|d Faculty of Biotechnology , Atma Jaya Catholic University of Indonesia , Jakarta 12930 , Indonesia.
authors.forename: Vivitri D
authors.initials: VD
authors.lastname: Prasasty
authors.affiliation: b Biomolecular NMR Laboratory , The University of Kansas , Shankel Structural Biology Center, 2034 Becker Drive, Lawrence , KS 66045 , USA.
authors.forename: Asokan
authors.initials: A
authors.lastname: Anbanandam
authors.affiliation: c Department of Chemistry and Molecular Biosciences , The University of Kansas , Lawrence , KS 66047 , USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kuczera
authors.affiliation: a Department of Pharmaceutical Chemistry , The University of Kansas , 2095 Constant Avenue, Lawrence , KS 66047 , USA.
authors.forename: Teruna J
authors.initials: TJ
authors.lastname: Siahaan
mesh_terms: D001665:Binding Sites; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs
chemical_list: D015820:Cadherins; D010456:Peptides, Cyclic
keywords: E-cadherin binding; NMR; blood–brain barrier; cyclic HAV peptide; molecular dynamics