Molecular Mechanism Regarding Allosteric Modulation of Ligand Binding and the Impact of Mutations on Dimerization for CCR5 Homodimer

Abstract

In this work, we combined accelerated molecular dynamics (aMD) and conventional molecular dynamics (cMD) simulations coupled with the potential of mean force (PMF), correlation analysis, principal component analysis (PCA), and protein structure network (PSN) to study the effects of dimerization and the mutations of I52V and V150A on the CCR5 homodimer, in order to elucidate the mechanism regarding cooperativity of the ligand binding between two protomers and to address the controversy about the mutation-induced dimer-separation. The results reveal that the dimer with interface involved in TM1, TM2, TM3, and TM4 is stable for the CCR5 homodimer. The dimerization induces an asymmetric impact on the overall structure and the ligand-binding pocket. As a result, the two protomers exhibit an asymmetric binding to the maraviroc (one anti-HIV drug). The binding of one protomer to the drug is enhanced while the other is weakened. The PSN result further reveals the allosteric pathway of the ligand-binding pocket between the two protomers. Six important residues in the pathway were identified, including two residues unreported. The results from PMF, PCA, and the correlation analysis clearly indicate that the two mutations induce strong anticorrelation motions in the interface, finally leading to its separation. The observations from the work could advance our understanding of the structure of the G protein-coupled receptor dimers and implications for their functions.

Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity

“…66 Moreover, the computational study together with the site-direct muta-genesis study performed by Zhang et al revealed that the CCR5 homodimerization involved TM1, TM2, TM3, and TM4. 67 In the present study, considering the fact that the attachment point for the spacer of the bivalent ligands designed, that is, the 3′-methyl group on the 1,2,4-triazol moiety of maraviroc pointed toward TM1, TM2, and TM3, and the possible steric hindrance of extracellular loop 1 (ECL1) between TM2 and TM3, TM1/TM2 was therefore selected as the plausible dimer interface of the CCR5. An MOR-CCR5 heterodimer model in which TM5/6 of the MOR and TM1/2 of the CCR5 were selected as dimer interfaces in complexing with VZMC013 (Figure S6a) was inserted into a membrane-aqueous sodium chloride solution system (Figure S6b) and subjected to further MD simulations.…”

“…Thus, they speculated that other interfaces have a higher possibility to be the interface of the CCR5 . Moreover, the computational study together with the site-direct mutagenesis study performed by Zhang et al revealed that the CCR5 homodimerization involved TM1, TM2, TM3, and TM4 . In the present study, considering the fact that the attachment point for the spacer of the bivalent ligands designed, that is, the 3′-methyl group on the 1,2,4-triazol moiety of maraviroc pointed toward TM1, TM2, and TM3, and the possible steric hindrance of extracellular loop 1 (ECL1) between TM2 and TM3, TM1/TM2 was therefore selected as the plausible dimer interface of the CCR5.…”

Oligomerization-Enhanced Receptor–Ligand Binding Revealed by Dual-Color Simultaneous Tracking on Living Cell Membranes

“…The observation is consistent with and demonstrates previous work showing that GPCR dimers may exert allosteric effects on binding with ligands. 26,27 Another interesting work using molecular dynamics simulation 28 found that the binding pocket volume of the CCR5 monomer is 567 Å3. Upon dimerization, the pocket volume of the first subunit increases to 650 Å 3 , while that of the second subunit reduces to 412 Å 3 .…”

Exploring the Activation Mechanism of a Metabotropic Glutamate Receptor Homodimer via Molecular Dynamics Simulation

“…45 The contribution of van der Waals (vdW) free energy is stronger in the dimer bound by the glutamates than in the apo system, indicating that the main driving force for the dimerization is vdW interaction, similar to the class A GPCR dimers reported. 38 2.1.2. Important Interface Residues Contributing to the Dimerization.…”