Paper Citing NAMD - Abstract
Pang, Xue-qin; Liu, Jian-yong
GPCR A(2A)AR Agonist Binding and Induced Conformation Changes of Functional Switches
CHINESE JOURNAL OF CHEMICAL PHYSICS, 27:29-38, FEB 2014
Agonist binding of A(2A) adenosine receptor (A(2A)AR) shows protective effects against inflammatory and immune. Efforts are exerted in understanding the general mechanism and developing A(2A)AR selectively binding agonists. Using molecular dynamics (MD) simulations, we have studied the interactions between A(2A)AR and its agonist (adenosine), and analyzed the induced dynamic behaviors of the receptor. Key residues interacting with adenosine are identified: A63(2.61), 166(2.64), V84(3.32), L85(3.33), T88(3.36), F168(5.29), M177(5.38), L249(6.51), H250(6.52), and N253(6.55) interacting with adenosine with affinities larger than 0.5 kcal/mol. Moreover, no interaction between adenosine and L167(5.28) is observed, which supports our previous findings that L167(5.28) is an antagonist specific binding reside. The dynamic behaviors of agonist bound A(2A)AR are found to be different from apo-A(2A)AR in three typical functional switches: (i) tight "ionic lock" forms in adenosine-A(2A)AR, but it is in equilibrium between formation and breakage in apo-A(2A)AR; (ii) the "rotamer toggle switch", T88(3.36)/F242(6.44)/W246(6.48), adopted different rotameric conformations in adenosine-A(2A)AR and apo-A(2A)AR; (iii) adenosine-A(2A)AR has a flexible intracellular loop 2 (IC2) and alpha-helical IC3, while apo-A(2A)AR preferred alpha-helical IC2 and flexible IC3. Our results indicate that agonist binding induced different conformational rearrangements of these characteristic functional switches in adenosine-A(2A)AR and apo-A(2A)AR.
