Abstract
A web-based G-protein coupled receptor (GPCR) ab initio modeling platform has been developed to support scientists involved in internal in silico drug discovery projects. Starting from a target GPCR sequence, the ab initio modeling workflow predicts an ensemble of 3-dimensional (3D) receptor structures which can subsequently be used for structure- based drug design activities. The workflow used to develop the web-based tools integrates MembStruk and Modeler application packages with significant improvements and enhancements made to the former. The workflow enabled through the web-based user interface encompasses the following steps: a) prediction of the transmembrane (TM) regions using the target GPCR sequence and other similar sequences; b) initial packing of the TM-helices; c) optimization of the TM-helical bundles by translation, rotation, and relaxation of the helices; d) addition of intra- and extra-cellular loops; e) final refinement of the 3D receptor structures including side chains and loops. A wizard-like workflow approach implemented in web-based GPCR modeling tools hides the complexity involved in various modeling steps and guides the user through the calculation one step at a time starting from a target sequence to a set of predicted 3D structures. The successful implementation of the workflow is presented by modeling the human adenosine A2A receptor (AA2AR) structure without the bound ligand and comparing the predicted structure of the TM-helices with the recently reported X-ray crystal structure.
Keywords: A2a receptor, ab initio modeling, GPCR modeling, Structure-based drug design, Web-based tools, Workflow automation, G-protein coupled receptor, 3-dimensional, transmembrane, adenosine A2A receptor, X-ray crystal structure, crystallography, molecular dynamics, Eisenberg hydrophobicty, lipid bilayers, cell multiple method, 3D macromolecular structures, Portable Batch System, Linux cluster, rhodopsin like, metabotropic glutamate, pheromone, Root Mean Square Deviation, C atoms, canonical helix structure, dilauroylphosphatidylcholine
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