Summary The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G-protein coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related experimentally determined homology templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe.

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The dynamics of proteins in aqueous solution has been investigated through a massive approach based on ''state of the art'' molecular dynamics simulations performed for all protein metafolds using the four most popular force fields (OPLS, CHARMM, AMBER, and GROMOS). A detailed analysis of the massive database of trajectories (>1.5 terabytes of data obtained using Ϸ50 years of CPU) allowed us to obtain a robust-consensus picture of protein dynamics in aqueous solution.force field ͉ molecular dynamics ͉ molecular modeling ͉ protein structure

The use of multiple X-ray protein structures has been reported to be an efficient alternative for the representation of the binding pocket flexibility needed for accurate small molecules docking. However, the docking performance of the individual single conformations varies widely and adding certain conformations to an ensemble is even counterproductive. Here we used a very large and diverse benchmark of 1068 X-ray protein conformations of 99 therapeutically relevant proteins, first, to compare the performance of the ensemble and single conformation docking, and, secondly, to find the properties of best performing conformers that can be used to select a smaller set of conformers for ensemble docking. The conformer selection has been validated through retrospective virtual screening experiments aimed at separating known ligand binders from decoys. We found that the conformers co-crystallized with the largest ligands displayed high selectivity for binders, and when combined in ensembles they consistently provided better results than randomly chosen protein conformations. The use of ensembles encompassing between 3 to 5 experimental conformations consistently improved the docking accuracy and binders vs. decoys separation.