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Journal of Biomedicine and Biotechnology
Volume 2012, Article ID 789741, 12 pages
http://dx.doi.org/10.1155/2012/789741
Research Article

Molecular Modeling of the M3 Acetylcholine Muscarinic Receptor and Its Binding Site

1Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya, 08028 Barcelona, Spain
2Centre de Biotecnologia Molecular, Departament d’Enginyeria Quimica, Universitat Politècnica de Catalunya, 08222 Terrassa, Spain
3Laboratori de Medicina Computacional, Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain

Received 19 July 2011; Accepted 8 November 2011

Academic Editor: Alejandro Giorgetti

Copyright © 2012 Marlet Martinez-Archundia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The present study reports the results of a combined computational and site mutagenesis study designed to provide new insights into the orthosteric binding site of the human M3 muscarinic acetylcholine receptor. For this purpose a three-dimensional structure of the receptor at atomic resolution was built by homology modeling, using the crystallographic structure of bovine rhodopsin as a template. Then, the antagonist N-methylscopolamine was docked in the model and subsequently embedded in a lipid bilayer for its refinement using molecular dynamics simulations. Two different lipid bilayer compositions were studied: one component palmitoyl-oleyl phosphatidylcholine (POPC) and two-component palmitoyl-oleyl phosphatidylcholine/palmitoyl-oleyl phosphatidylserine (POPC-POPS). Analysis of the results suggested that residues F222 and T235 may contribute to the ligand-receptor recognition. Accordingly, alanine mutants at positions 222 and 235 were constructed, expressed, and their binding properties determined. The results confirmed the role of these residues in modulating the binding affinity of the ligand.