Targeting domain-III hinging of dengue envelope (DENV-2) protein by MD simulations, docking and free energy calculations

Abstract

The entry of the dengue virus is mediated by the conformational change in the envelope protein due to change in the endosomal pH. The structural study reveals that domain-III of the dengue envelope protein (DENV) shows the largest shift in its position during the entry of the virus. Therefore, targeting the hinge region of the domain-III may block the conformational changes in the DENV. In the present work, we have targeted the domain I/III hinge region using four known ligands used for the dengue envelope protein (serotype-2) and have intended to explore the specificity of one ligand R1 (5-(3-chlorophenyl)-N-(2-phenyl-2H-benzo[d][1,2,3]triazol-6-yl)furan-2-carboxamide) that succeeded the dengue inhibition by the molecular dynamics (MD) simulations in conjunction of the molecular docking and the binding free energy calculations. The residue interactions map shows Lys 296 of domain-III of the DENV-2, which might be responsible for binding small molecules between domain I/III interface, as an important residue conserved in all the dengue serotypes.

Recent Developments and Applications of the MMPBSA Method

“…For anti-viral applications, research efforts were focused on analyzing interactions for ankyrin and domain III of the envelope protein of dengue virus II (Chong et al, 2015 ; Dubey et al, 2017 ), a modular capsomere of a murine polyomavirus (MPV) VLP designed to protect against influenza (Zhang L. et al, 2014 ), antibody recognition of immunoglobulin 2D1 for influenza virus H1N1 (Leong et al, 2015 ), differential structural dynamics and antigenicity of two HA-specific CTL epitopes binding to HLA-A * 0201 for influenza virus H5N1 (Sun and Liu, 2015 ), a complex of histone deacetylase 6 and ubiquitin-specific protease 5 for influenza virus A (Passos et al, 2016 ), and for a complex of an antibody and epitope variant of HIV-1 p24 capsid protein (Karim et al, 2015 ). For antibacterial applications, there were studies of salamander PGRP1 with its splice variant adPGRP1a for the innate immune system (Qi Z. T. et al, 2017 ), and an adsorption mechanism of human beta-defensin-3 on bacterial membranes (Lee et al, 2016 ).…”

Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation

“…As stated by Schön et al, the antiviral properties of HIV-1 entry inhibitors are reflected by the thermodynamics of these inhibitors; we used the MM-GB/SA method [32,33] for the calculations of thermodynamic parameters and free energy of binding. The principles of these methods are well established [34,35] and have been successfully applied for the class II fusion viruses in the previous studies [36][37][38]. For all MMGBSA calculations, we used the most populated MD trajectories obtained from clustering of trajectories (100 ns).…”

Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation

“…As stated by Schӧn et al, the antiviral properties of HIV-1 entry inhibitors are reflected by the thermodynamics of these inhibitors, we used MM-GB/SA method [32][33] for the calculations of thermodynamic parameters and free energy of binding. The principles of these methods are well established [34][35] and have been successfully applied for the class II fusion viruses in the previous studies [36][37][38] . Note that all energetics are calculated for the most populated frames of MD trajectories obtained from cluster analysis as described above.…”