Abstract:
Allosteric interactions have been thought to be of great importance in regulating the gating mechanism of the receptors. The term allostery comes from the Greek words allos, "other," and stereos, "shape”, meaning that action in one part of the molecule causes an effect at another site. Acetylcholine has been one of the first identified neurotransmitters. It is a chemical transmitter existing in the nervous system of many organisms including humans. In this work, allostery and allosteric pathways in the information transmission between Acetylcholine binding and the gate regions have been studied on three structures. These three structures are Acetylcholine Binding Protein, nicotinic Acetylcholine Receptor and the Ligand Binding Domain of nicotinic Acetylcholine Receptor without the transmembrane region. For this, combined computational methodologies have been employed. In understanding of the allostery; Gaussian Network Model (GNM) and Anisotropic Network (ANM) have been performed to study the fluctuations of residues and the correlation between them in various modes of motion. The results of the correlation analysis by GNM are elaborated using MCPOOL program. MCPOOL identifies allosteric pathways between a starting and a selected target region. These regions have been examined with respect to the dynamic mode shapes of GNM and ANM analyses and the conservation and the correlated mutational analysis. ANM has been applied to see three dimensional conformational changes of molecule in different modes. Changes in diameter of gate region in different modes of motion have been presented by HOLE program. Results suggest that Loop 2, Cys Loop and Loop 9 are mostly visited regions in the allosteric communications, which agree with experimental results and also suggest new regions that might be important. These regions overlap with the minimum points of the slowest mode shapes. The conservation and correlated mutations analyses shows that some of the mostly visited residues along the paths are either conserved or correlated during the evolution. The presence of the transmembrane domain in the calculations contributes to the pathways and the motion of the structure. Indeed, without the transmembrane regions, the ligand binding domain can not lead to a conformational change which contributes to the twisting motion of the receptor, which is an essential movement for the gating mechanism.
