Benchmarking of dimeric threading and structure refinement

Abstract

The understanding of proteinprotein interactions is a major goal in the postgenomic era. The prediction of interaction from sequence and the subsequent generation of fulllength dimeric models is therefore of great interest especially because the number of structurally characterized protein-protein complexes is sparse. A quality assessment of a benchmark comprised of 170 weakly homologous dimeric target-template pairs is presented. They are predicted in a two-step method, similar to the previously described MULTI-PROSPECTOR algorithm: each target sequence is assigned to a monomeric template structure by threading; then, those templates that belong to the same physically interacting dimer template are selected. Additionally we use structural alignments as the "gold standard" to assess the percentage of correctly assigned monomer and dimer templates and to evaluate the threading results with a focus on the quality of the alignments in the interfacial region. This work aims to give a quantitative picture of the quality of dimeric threading. Except for one, all monomer templates are identified correctly, but approximately 40% of the dimer templates are still problematic or incorrect. Preliminary results for three full-length dimeric models generated with the TASSER method show on average a significant improvement of the final model over the initial template. Proteins 2006;63:457-465.

Refining homology models by combining replica‐exchange molecular dynamics and statistical potentials

“…Baker and coworkers2 for example reported encouraging results for 5 of 16 small proteins using a refinement protocol in which multiple rounds of random torsion‐angle perturbation and Monte Carlo (MC) relaxation were performed on low‐resolution models built from a set of sequence homologues of the target protein using the standard fragment insertion approach from ROSETTA 53. Another method based on fragment assembly and MC simulation is TASSER,54 which has been applied to the refinement of NMR structures55 and dimeric structural models 56. Recently, these ab initio approaches have also been applied to the refinement of homology models.…”

Homology-based modeling of 3D structures of protein–protein complexes using alignments of modified sequence profiles

“…This method was recently extended to combine experimental and numerical techniques to predict the domain-domain complexes in yeast [14]. Skolnick and coworkers use threading techniques to predict the structures of full-length protein complexes [15]. MULTIPROSPECTOR [16] threads the two target sequences onto each structure in a representative, non-redundant library of folds.…”

Protein docking using case‐based reasoning

“…Several groups, including ourselves, have described homology‐based protein‐protein interaction (PPI) modeling approaches. For example, Lu et al ., Grimm et al ., Launay and Simonson, and Mukherjee and Zhang used threading techniques to predict the 3D structure of a complex starting from the sequences of the component proteins and a library of known complexes. Korkin et al .…”