Todd J. Taylor

Assessment of template‐free modeling in CASP10 and ROLL

We present the assessment of predictions for Template‐Free Modeling in CASP10 and a report on the first ROLL experiment wherein predictions are collected year round for review at the regular CASP season. Models were first clustered so that duplicated or very similar ones were grouped together and represented by one model in the cluster. The representatives were then compared with targets using GDT_TS, QCS, and three additional superposition‐independent score functions newly developed for CASP10. For each target, the top 15 representatives by each score were pooled to form the Top15Union set. All models in this set were visually inspected by four of us independently using the new plugin, EvalScore, which we developed with the UCSF Chimera group. The best models were selected for each target after extensive debate among the four examiners. Groups were ranked by the number of targets (hits) for which a groups model was selected as one of the best models. The Keasar group had most hits in both categories, with four of 19 FM and eight of 36 ROLL targets. The most successful prediction servers were QUARK from Zhangs group for FM category with three hits and Zhang‐server for the ROLL category with seven hits. As observed in CASP9, many successful groups were not true “template‐free” modelers but used remote templates and/or server models to obtain their winning models. The results of the first ROLL experiment were broadly similar to those of the CASP10 FM exercise. Proteins 2014; 82(Suppl 2):57–83.

Discrimination of thermophilic and mesophilic proteins

BackgroundThere is a considerable literature on the source of the thermostability of proteins from thermophilic organisms. Understanding the mechanisms for this thermostability would provide insights into proteins generally and permit the design of synthetic hyperstable biocatalysts.ResultsWe have systematically tested a large number of sequence and structure derived quantities for their ability to discriminate thermostable proteins from their non-thermostable orthologs using sets of mesophile-thermophile ortholog pairs. Most of the quantities tested correspond to properties previously reported to be associated with thermostability. Many of the structure related properties were derived from the Delaunay tessellation of protein structures.ConclusionsCarefully selected sequence based indices discriminate better than purely structure based indices. Combined sequence and structure based indices improve performance somewhat further. Based on our analysis, the strongest contributors to thermostability are an increase in ion pairs on the protein surface and a more strongly hydrophobic interior.

Assessment of CASP10 contact‐assisted predictions

In CASP10, for the first time, contact‐assisted structure predictions have been assessed. Sets of pairs of contacting residues from target structures were provided to predictors for a second round of prediction after the initial round in which they were given only sequences. The objective of the experiment was to measure model quality improvement resulting from the added contact information and thereby assess and help develop so‐called hybrid prediction methods—methods where some experimentally determined distance constraints are used to augment de novo computational prediction methods. The results of the experiment were, overall, quite promising. Proteins 2014; 82(Suppl 2):84–97.

Definition and classification of evaluation units for CASP10.

For the 10th experiment on Critical Assessment of the techniques of protein Structure Prediction (CASP), the prediction target proteins were broken into independent evaluation units (EUs), which were then classified into template‐based modeling (TBM) or free modeling (FM) categories. We describe here how the EUs were defined and classified, what issues arose in the process, and how we resolved them. EUs are frequently not the whole target proteins but the constituting structural domains. However, the assessors from CASP7 on combined more than one domain into 1 EU for some targets, which implied that the assessment also included evaluation of the prediction of the relative position and orientation of these domains. In CASP10, we followed and expanded this notion by defining multidomain EUs for a number of targets. These included 3 EUs, each made of two domains of familiar fold but arranged in a novel manner and for which the focus of evaluation was the interdomain arrangement. An EU was classified to the TBM category if a template could be found by sequence similarity searches and to FM if a structural template could not be found by structural similarity searches. The EUs that did not fall cleanly in either of these cases were classified case‐by‐case, often including consideration of the overall quality and characteristics of the predictions. Proteins 2014; 82(Suppl 2):14–25.

Protein Structural Domain Assignment with a Delaunay Tessellation Derived Lattice

We describe a fully automated method of protein structural domain assignment using a Potts model which we call DePot (an abbreviation for Delaunay-Potts). It is a heavily modified version of a method described previously by WR Taylor. Each amino acid residue is represented as a site in an irregular lattice derived from the Delaunay tessellation of the protein structure. Domain membership is represented by a spin value and each site has a spin which can change under the influence of its neighbors. Spins are allowed to interact subject to an Ising ferromagnetic-like energy function until clusters of like spins emerge and these clusters define domains. DePot is simple and easy to implement and the assignments agree well with previously published methods.

Discrimination and Classification of Thermophilic and Mesophilic Proteins

There has been considerable interest in the physical basis for the increased thermostability of thermophilic proteins with respect to their mesophilic counterparts since the discovery of highly heat tolerant organisms. We have systematically studied several large sets of protein structures in order to find those properties with the most power to discriminate mesophilic proteins from their thermophilic orthologs and then to classify proteins based on sequence and structural properties. Most of the structure-based descriptors used in our discrimination and classification experiments were derived from the Delaunay tessellations of the protein structures.

Statistical Geometry and Topology of Real and Model Protein Structures

We have subjected several sets of real and simplified model proteins to Delaunay tessellation and have computed statistics on both Delaunay simplex geometry and the tendency of quadruplets of residue types to be joined together in simplices. We have characterized the geometry and contact patterns of real proteins and some of the ways in which they differ from these model structures. We have also found heretofore unreported asymmetries in contact patterns among residue quadruplets joined in simplices in real proteins.

A new method of secondary structure assignment based on the Delaunay tessellation of protein structures

A five element descriptor derived from the Delaunay tessellation of a protein structure can be assigned to each residue in the protein. The descriptor characterizes main chain topology in the neighborhood of the residue. Rules which accurately map it to the DSSP secondary structure assignment can be devised, which is surprising because the descriptor does not explicitly depend on any angles, lengths, areas, or putative hydrogen bonds, nor does it contain information on internal residue geometry.