Abstract
VE-cadherin is a protein in the cadherin family tha t is found at the adherens junctions of the microve ssel endothelial cells of the Blood-Brain Barrier (BBB). It is recognized as the homotypic cell adhesion molecules and there is limited structural informati on on how VE-cadherins mediate cell-cell adhesion. It has been shown that the EC1 domain of cadherins is important for the homophilic interactions for cell-cell adhesion. Therefore, the aims of this study are to model the structure of the EC1 domain of VE-cadherin, study its molecular dynamics properties and evaluat e its interactions with cadherin peptides. In this study, the sequence alignment between EC1 domain of VE-cadherin and the template protein were conducted by CLUSTALW2 platform. The SWISS-MODEL platform performed the homology modeling of the EC1 domain of VE-cadherin structure. Structural refinem ent was done by using KOBAMIN. Some validation analysis platforms also were conducted included PROCHECK, VERIFY3D, ERRAT and MOLPROBITY to check the allowed residues region in Ramachandran Plot (RP) and the quality of the structure. The m ost favored region was found 95.5% in RP value and overall model structure quality is 71.34%. Molecular Dynamics (MD) was run under CABS-FLEX to determine the flexibility of the residue index. The RMSD value of MD is 1.5A per residue index. Eventually, molecular docking by AUTODOCK VINA was conducted to investigate protein-ligand interaction . From docking, it is found that the affinity energ y is -4.8 kcal/mol which has the most favorable binding of EC1 domain with the peptide.
Highlights
The difficulty of delivering drugs to the brain is due to the presence of the Blood-Brain Barrier (BBB)
VE-cadherin is a protein in the cadherin family that is found at the adherens junctions of the microvessel endothelial cells of the Blood-Brain Barrier (BBB)
HAV6 peptide increases the in vivo brain delivery of GdDTPA, R800 Near-IR (NIR) dye and R800cw-PEG molecules (MW 25 KDa) into the brain of Balb/c mice as detected by magnetic resonance imaging and NIR imaging (On et al, 2014). These results suggested that modulation of cadherin-cadherin interactions in the adherens junction can increase the porosity of the paracellular pathway of the BBB (Prasasty et al, 2014)
Summary
The difficulty of delivering drugs to the brain is due to the presence of the Blood-Brain Barrier (BBB). The BBB consists of microvessel endothelial cells that deliver nutrients to the brain; BBB prevents most drug molecules from entering the brain to make it difficult to treat drug brain diseases. The drug molecules cannot readily partition into the cell membranes to cross the BBB. The presence of metabolic enzymes and efflux pumps (i.e., P-glycoprotein (Pgp) and Multidrug Resistance Proteins (MRPs)) inhibits drug molecules from crossing the BBB via transcellular pathway. Drug molecules can penetrate through the paracellular pathways of the BBB; this pathway is limited by the presence of the tight intercellular juctions (Trivedi et al, 2012; Zheng et al, 2006).
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