Computational approaches for modeling GPCR dimerization

Abstract

Growing experimental evidences suggest that dimerization and oligomerization are important for G Protein- Coupled Receptors (GPCRs) function. The detailed structural information of dimeric/oligomeric GPCRs would be very important to understand their function. Although it is encouraging that recently several experimental GPCR structures in oligomeric forms have appeared, experimental determination of GPCR structures in oligomeric forms is still a big challenge, especially in mimicking the membrane environment. Therefore, development of computational approaches to predict dimerization of GPCRs will be highly valuable. In this review, we summarize computational approaches that have been developed and used for modeling of GPCR dimerization. In addition, we introduce a novel two-dimensional Brownian Dynamics based protein docking approach, which we have recently adapted, for GPCR dimer prediction.

Fig. 1

GPCR Oligomeric Interface. A. Squid rhodopsin, TM4/TM5-TM4/TM5 (PDBID:2Z73); B. Squid rhodopsin, TM5-TM5 (PDBID:2Z73); C. Histamine H1 receptor, TM4-TM4 (PDBID: 3RZE); D. μ-OR, TM1/TM2/H8-TM1/TM2/H8, TM5/TM6-TM5/TM6 (PDBID:4DKL); E. β₁-AR homo oligomers, TM1/TM2/H8-TM1/TM2/H8 , TM4/TM5-TM4/TM5 (PDBID: 4GPO). (Color coded figures are available for the web version of this article)

Fig. 2

Hybrid electrostatic potential map of membrane and water for electrostatic interaction calculations for 2D-BD simulations. The arrows present additional relaxations of motions perpendicular to the membrane and rotation out of the membrane, as a suitable approximation or simulations of membrane proteins that translate and rotate within the two-dimensional membrane.

Fig. 3

The center of mass distribution of Monomer II (gray balls) around Monomer I of β1-adrenergic receptor from 2D-BD simulations (Left: top view, Right: side view). The center of mass of crystal structure of Monomer II is shown as a black ball.

Fig. 4

Interaction energy (score) vs. RMSD between the predicted and crystal structures. (A) Structures from BD simulations followed by rigid body energy minimization. The sampled complexes near to crystal dimer are marked with an orange rectangular box. (B) 23 reprehensive structures of the cluster from the top 200 lowest energy predicted structures. The lowest energy predicted complex is marked with an orange arrow (RMSD = 0.49 Å from the crystal structure).

Fig. 5

Comparison of crystal structure and 2D-BD predicted structure. The BD predicted Monomer II (right, in black) is very close to that of the crystal structure (right, in gray), and Monomer I (left) in colored in gray (RMSD: 0.49 Å)