Homology modeling of human CCR5 and analysis of its binding properties through molecular docking and molecular dynamics simulation

Abstract

In this study, homology modeling, molecular docking and molecular dynamics simulation were performed to explore structural features and binding mechanism of some inhibitors of chemokine receptor type 5 (CCR5), and to construct a model for designing new CCR5 inhibitors for preventing HIV attachment to the host cell. A homology modeling procedure was employed to construct a 3D model of CCR5. For this procedure, the X-ray crystal structure of bovine rhodopsin (1F88A) at 2.80Å resolution was used as template. After inserting the constructed model into a hydrated lipid bilayer, a 20ns molecular dynamics (MD) simulation was performed on the whole system. After reaching the equilibrium, twenty-four CCR5 inhibitors were docked in the active site of the obtained model. The binding models of the investigated antagonists indicate the mechanism of binding of the studied compounds to the CCR5 obviously. Moreover, 3D pictures of inhibitor-protein complex provided precious data regarding the binding orientation of each antagonist into the active site of this protein. One additional 20 ns MD simulation was performed on the initial structure of the CCR5-ligand 21 complex, resulted from the previous docking calculations, embedded in a hydrated POPE bilayer to explore the effects of the presence of lipid bilayer in the vicinity of CCR5-ligand complex. This article is part of a Special Issue entitled Protein translocation across or insertion into membranes.

Joint-based description of protein structure: its application to the geometric characterization of membrane proteins

“…For example, the Ramachandran plot is built in the PROCHECK 3 and WHAT_CHECK 4 to verify the stereochemical quality of the protein structure. Recently, it has been used widely to validate the protein structure generated from homology modeling 5 within the frame of molecular dynamics simulations.…”

A Study on the Binding of Loperamide to Human Serum Albumin Using Combination of Computational and Experimental Methods

“…Molecular dynamics (MD) simulation is one of the best methods for understanding the physical basis of ligand binding process, changes in structure and function of macromolecules in atomistic details. MD calculation can be also used as a powerful tool for study the binding structures and recognize the best binding mode [12,[41][42][43][44]. To study the stability of the studied system (HSA, LOP, water, ions, etc.…”

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“…Then the molecules were minimized using Tripos force field, Gasteiger-Huckel charges were added and used convergence criterion of 0.005 kcal/mol Å. Molecular Docking study was performed to all the synthesized molecules separately by using AutoDock4.2 program, using the Lamarckian Genetic Algorithm (LGA) and implemented empirical free energy function. 29 Initially, the modelled protein was loaded and polar hydrogen were added. The molecule was loaded and set conformations and saved it in PDBQT format and then saved generated PDB file to PDBQT format.…”