Paper Citing NAMD - Abstract
Mahmood, Md. Iqbal; Liu, Xinli; Neya, Saburo; Hoshino, Tyuji
Influence of Lipid Composition on the Structural Stability of G-Protein Coupled Receptor
CHEMICAL & PHARMACEUTICAL BULLETIN, 61:426-437, APR 2013
beta(2) Adrenergic receptor (beta(2)AR) is a kind of G-protein coupled receptors (GPCRs) which transduce a wide range of extracellular signals into intracellular messages responsible for the regulation of diverse cell functions. Because of their functional ubiquity, GPCR is one of the most important drug targets in pharmaceutical industry. Although recent crystallographic studies provided both the active and the inactive states of some families of GPCRs, the influence of lipid composition of bilayer membrane on their activation is still poorly understood. In this work, we address the influence of lipid composition on the structural stability of GPCR, performing molecular dynamics simulations of three kinds of states: apo-, and agonist epinephrine-, or antagonist alprenolol-bound beta(2)AR. These three kinds of beta(2)ARs were embedded in four types of lipid membranes: (i) pure palmitoyl-oleoyl-phosphatidyl-choline (POPC), (ii) POPC/cholesterol (CHL), (iii) POPC/CHL/GM1 (GM1 ganglioside), (iv) POPC/palmitoyl-oleoyl-phosphatidyl-ethanolamine (POPE)/CHL/sphingomyeline (SM). The side chains of Lys267(6.29) and Asp331(7.58) showed different conformations among the three states in all types of lipid membranes. The distances between Lys267(6.29) and Asp331(7.58) of apo- and alprenolol-bound beta(2)ARs are smaller than that of the epinephrine-bound beta(2)AR. In contrast beta(2)ARs in POPC/CHL bilayer were unstable in which the salt bridge; i.e., ionic lock, was not formed between Arg131(3.50) and Glu268(6.30). We have also examined the distribution of lipid molecules. A stable hydrophobic interaction between CHL and beta(2)AR was observed at transmembrane helix5 in POPC/CHL/GM1 and POPC/POPE/CHL/SM membranes. These results suggest that the lipid composition strongly affects the conformation of GPCR and essentially concerns the GPCR activation.
