Investigation of Inhibition Mechanism of Chemokine Receptor CCR5 by Micro-second Molecular Dynamics Simulations.

Ramin Ekhteiari Salmas,Mine Yurtsever,Serdar Durdagi

doi:10.1038/srep13180

Ramin Ekhteiari Salmas, Mine Yurtsever + Show 1 more

Open Access

https://doi.org/10.1038/srep13180

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Abstract

Chemokine receptor 5 (CCR5) belongs to G protein coupled receptors (GPCRs) and plays an important role in treatment of human immunodeficiency virus (HIV) infection since HIV uses CCR5 protein as a co-receptor. Recently, the crystal structure of CCR5-bound complex with an approved anti-retroviral drug (maroviroc) was resolved. During the crystallization procedure, amino acid residues (i.e., Cys224, Arg225, Asn226 and Glu227) at the third intra-cellular loop were replaced by the rubredoxin for stability reasons. In the current study, we aimed to understand the impact of the incorporated rubredoxin on the conformations of TM domains of the target protein. For this reason, rubredoxin was deleted from the crystal structure and the missing amino acids were engineered. The resultant structure was subjected to long (μs) molecular dynamics (MD) simulations to shed light into the inhibitory mechanism. The derived model structure displayed a significant deviation in the cytoplasmic domain of TM5 and IC3 in the absence of rubredoxin. The principal component analyses (PCA) and MD trajectory analyses revealed important structural and dynamical differences at apo and holo forms of the CCR5.

Highlights

The V3 loop of envelope glycoprotein is critical in human immunodeficiency virus (HIV) fusion when it links to the co-receptor[20]
Despite of many potential investigations on HIV field, many questions regarding the interactions between gp[120] and CCR5 is still not solved: How gp[120] uses CCR5 as a co-receptor to enter the human cell? What is the molecular mechanism of this event? How anti HIV drugs in the position of CCR5 inhibitors protect the coupling of gp[120] and Extra cellular (EC) domains of the CCR5? So far, most of the in silico studies on CCR5 were based on homology models[24,25,26,27]
We showed that the rubredoxin co-crystallized with the protein had a significant impact on the structure especially on the cytoplasmic side of TM5

Summary

Introduction

The V3 loop of envelope glycoprotein ( gp120) is critical in HIV fusion when it links to the co-receptor[20]. Tamamis et al.[28] used the CCR5 X-ray structure for investigation of the molecular recognition of CCR5 by a dual tropic HIV-1 gp[120] V3 loop via short (20 ns) MD simulations. We aimed to understand better the molecular mechanism of CCR5-drug interactions via long (0.6 μ s in total) MD simulations. The analyses such as principle component analysis (PCA) and clustering approach were performed to eliminate the insignificant dynamic modes and the conformational changes throughout the simulations and to explore the structural differences between the apo and holo forms of the CCR5

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