Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Effect of template selection on the construction of atomistic models of GPCRs by homology modeling
Analysis of the diverse crystallographic structures of G-Protein Coupled Receptors (GPCRs) available suggests that although they share a common seven helix bundle, there are specific features that might be relevant for ligand design. Despite the number of crystallographic structures of GPCRs is steadily increasing, there are still challenges that hamper the availability of new ones. In the absence of a crystallographic structure for a specific receptor, homology modeling remains one of the most important techniques for constructing 3D models of proteins.
In the present study we have investigated the use of molecular dynamics of the GPCR embedded in a lipid bilayer as refinement process for models produced by homology modeling. For this purpose we selected the known structure of a GPCR as reference and produced several models by homology modeling followed by a molecular dynamics refinement process. Specifically, we investigated the effect of template selection, mode of refinement (with or without ligand) as well as the effect of the sampling time. Models produced were subsequently compared with the crystallographic structure. Specifically, we report the results of a comparison study of different models of the M3 muscarinic receptor produced by homology modeling using diverse templates including the M2 muscarinic receptor; the histamine H1 and rhodopsin; with or without ligands bound in the refinement process as well as the effect of sampling time. Results suggest that molecular dynamics of the protein embedded in a lipid bilayer improves the homology models as previously suggested . Moreover, the accuracy of the model greatly depends on the proximity of the template and the target in the phylogenetic tree for the same simulation time. Finally, although the presence of a ligand produces a faster equilibration of the system, after a long trajectory accuracy of the structure produced is comparable to the model refined without ligand.
I. Kufareva, V. Katritch, Participants of GPCR Dock 2013, R. C. Stevens, and R. Abagyan (2014). Advances in GPCR Modeling Evaluated by the GPCR Dock 2013 Assessment: Meeting New Challenges. Structure 22 1120-1139.
Cecylia S. Lupala
Department of Chemical Engineering