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Different Environments for a Realistic Simulation of GPCRs‐Application to the M 2 Muscarinic Receptor
Author(s) -
Jöhren Kirstin,
Höltje HansDieter
Publication year - 2005
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200400992
Subject(s) - muscarinic acetylcholine receptor , chemistry , biophysics , transmembrane protein , g protein coupled receptor , bilayer , transmembrane domain , ligand (biochemistry) , receptor , molecular dynamics , lipid bilayer , antagonist , membrane , crystallography , biochemistry , computational chemistry , biology
A model of the human M 2 muscarinic receptor was taken as an example for a class A G‐protein coupled receptor to explore the influence of different environments in a molecular dynamics simulation (MDS) on the protein structure. The most commonly used environment is the vacuum, although it is very unnatural for a transmembrane protein. As an alternative a membrane‐like system, consisting of a lipophilic central layer and two aqueous flanking layers, was tested. The most realistic system that can be applied is a phospholipid bilayer with a surrounding physiological sodium chloride solution. From all systems good protein structures were received, nevertheless clear differences between the systems were detected in the structural comparison of the models. Subsequently it was analyzed whether the observed structural differences influence ligand binding. For this purpose the antagonist (S)‐scopolamine was docked into the binding cavity, which is well known by many reported single and multiple point mutations. As expected from the observed structural variations triggered by the type of environment employed in MDS, also differences in the binding mode of (S)‐scopolamine were detected, all contacts, however, which are known to be important were found.