COMP 104 |
| G-protein-coupled receptors (GPCRs) are a large and functionally diverse superfamily of helical transmembrane proteins that play a key role in signal transduction and represent important therapeutic targets in many diseases. Due to high sequence divergence within the family, and a lack of high-resolution structure except for one member of the family, deriving realistic structural models for GPCRs has been a chanllenging protein folding problem. We present a two-step modeling protocol for the transmembrane domains of family A GPCRs that initially packs the seven transmembrane helices by restrained molecular dynamics using system-specific distance restraints, then extensively refines the helix bundle with implicit membrane generalized Born model and replica exchange sampling. System-specific distance restraints are imposed between pairs of residues predicted to be in contact from sequence conservation analysis. We find that this method is able to generate models that agree with many of the available experimental data from ligand-binding. We believe this approach addresses issues in efficiently sampling alternative conformations for building the correct helix-helix interfaces within the helix bundle. |
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Bold Predictions in Theoretical Chemistry: A Poster Session in Honor of One of the Boldest, Bill Goddard, on the Occasion of his 70th Birthday
7:30 PM-9:30 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Computers in Chemistry |