TagDock: An Efficient Rigid Body Docking Algorithm for Oligomeric Protein Complex Model Construction and Experiment Planning

Abstract

We report here new computational tools and strategies to efficiently generate three-dimensional models for oligomeric biomolecular complexes in cases where there is limited experimental restraint data to guide the docking calculations. Our computational tools are designed to rapidly and exhaustively enumerate all geometrically possible docking poses for an oligomeric complex, rather than generate detailed, atomic-resolution models. Experimental data, such as inter-atomic distance measurements, are then used to select and refine docking poses that are consistent with the experimental restraints. Our computational toolkit is designed for use with sparse datasets to generate intermediate-resolution docking models, and utilizes distance difference matrix analysis to identify further restraint measurements that will provide maximum additional structural refinement. Thus, these tools can be used to help plan optimal residue positions for probe incorporation in labor-intensive biophysical experiments such as chemical crosslinking, EPR, or FRET spectroscopy studies. We present benchmark results for docking the collection of all 176 heterodimer protein complexes from the ZDOCK database, as well as a protein homodimer with recently collected experimental distance restraints, to illustrate the toolkit’s capabilities and performance, and to demonstrate how distance difference matrix analysis can automatically identify and prioritize additional restraint measurements that allow us to rapidly optimize docking poses.

Structural reorganization of the chromatin remodeling enzyme Chd1 upon engagement with nucleosomes

“…In the first approach, a conjugated gradient minimisation was carried with centres of the modelled distribution of the nitroxide atoms NOE constraints in Xplor-NIH ( Schwieters et al, 2003 ) ( Figure 2C ). In the second, TagDock ( Smith et al, 2013 ) was used to compute all geometrically possible docking poses between the domains and evaluated those compatible with experimental distance constraints. The docking poses that are consistent with the constraints are then further refined.…”

“…In addition to the XPLOR-NIH approach, the Tagdock program ( Smith et al, 2013 ) was used to perform distance restrained rigid docking calculations. In brief, 100,000 decoys were generated during the first low-resolution docking phase with a random starting orientation.…”

“…In brief, 100,000 decoys were generated during the first low-resolution docking phase with a random starting orientation. A Boltzmann-weighted MTSSL rotamer library ( Smith et al, 2013 ) was utilised for the respective spin labelled positions. A score for the docked complex was calculated based on the experimental distance restraints.…”

Structural reorganization of the chromatin remodeling enzyme Chd1 upon engagement with nucleosomes

“…In the first, the distribution was used to align the centres of the modelled distribution of the MTSL label using Xplor-NIH (Schwieters et al, 2003) ( Figure 2C). In the second, TagDock (Smith et al, 2013) was used to fit the distribution of experimentally determined distances to the distribution of modelled spin label locations ( Figure 2D). After 500 runs the RMS deviation of the solutions for the Xplor and TagDock based solutions were 2.8 and 1.6 Å respectively.…”

Automated Structure Refinement for a Protein Heterodimer Complex Using Limited EPR Spectroscopic Data and a Rigid-Body Docking Algorithm: A Three-Dimensional Model for an Ankyrin-CDB3 Complex

“…We have previously developed the TagDock software package to treat rigid body docking problems. 9 Here, we describe an enhanced version of the TagDock software suite, which now includes an MTSSL side-chain rotamer library to facilitate explicit spin label modeling in the protein docking calculations. To illustrate the utility of these TagDock enhancements, we present results for detailed structural refinement of an important human erythrocyte cytoskeletal complex formed between ankyrin-R and the cytosolic domain of anion exchange protein AE1, or band 3 (CDB3), using EPR pair distance measurements and spin-label accessibility data 10 to filter candidate complex models.…”