Amresh Prakash, Pratibha Mehta, Luthra
Medicinal Chemistry Division, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, North Campus, Mall Road, Delhi 110007, India.
The structural and dynamic information of A 2A R-D 2 R could provide a more complete understanding of the molecular and energetic basis of GPCR oligomerization, thus facilitating the design of novel GPCR oligomer-specific drugs. The biochemical and functional study suggested the A 2A R-D 2 R interactions may provide new therapeutic target for Parkinson’s disease. In the present work, the analysis of structure-based features (e.g., Alpha, Beta, SurfAlpha, and SurfBeta; GapIndex, Leakiness and Gap Volume) with implementation of slow mode analysis (ENM) facilitated the prediction of kinetics (K off , K on , and K d ) of A 2A R-D 2 R protein-protein interaction. Kinetic constant of A 2A R-D 2 R has been predicted to address the association-dissociation of A 2A R-D 2 R complex using slow mode elastic network model showed correlation coefficient of K d and K on was 0.294 and the correlation coefficient of K d and K off was 0.635 describe stable interfacial contact of dimmer. The results demonstrated the stable hetromerization (association; Kslow) between the A2AR and D 2 R, and presumed that interfaces contacts depended on the coulombic interaction between the D 2 R intracellular loops (ICLs) and C-terminal tails of the A2AR. Structural dynamic properties study, ENM and KFC server based hot-spot analysis illustrated the stoichiometry of (A 2A R-D 2 R) contact interfaces as dimmer. The propensity of surface amino acid involved in interaction illustrated the presence of positively (Arg, R; His, H; and Lys,K) and negatively (Glu, E) and Asp, D) charged structural motif of TMs and ICL3 of A 2A R and D 2 R with significant columbic forces at interface of dimmer contact crystal structure. Read More …