One contact for every twelve residues allows robust and accurate topology-level protein structure modeling

Abstract

A number of methods have been described for identifying pairs of contacting residues in protein three-dimensional structures, but it is unclear how many contacts are required for accurate structure modeling. The CASP10 assisted contact experiment provided a blind test of contact guided protein structure modeling. We describe the models generated for these contact guided prediction challenges using the Rosetta structure modeling methodology. For nearly all cases, the submitted models had the correct overall topology, and in some cases, they had near atomic-level accuracy; for example the model of the 384 residue homo-oligomeric tetramer (Tc680o) had only 2.9 Å root-mean-square deviation (RMSD) from the crystal structure. Our results suggest that experimental and bioinformatic methods for obtaining contact information may need to generate only one correct contact for every 12 residues in the protein to allow accurate topology level modeling.

Keywords: ab initio prediction; comparative modeling; contact prediction; homology modeling; protein structure prediction; rosetta.

Figure 1

Schematic representation of the protocol used for contact assisted structure prediction. The protocol consists of two stages. In the first stage (Topology Determination), topologies and partial structures with satisfied contacts and good secondary structure were obtained from (A) Rosetta ab initio sampling methods with constraints, (B) partial threaded models from the top 1000 SPARKS-X alignments, and (C) Rosetta non-local fragment pairs. For some targets, beta-strand pairings were predicted from either (B) or (C) and enforced using the Rosetta broken chain fold-tree structure prediction method. In the second stage (Topology Refinement), the models and partial structures predicted from the first stage were used as input for the RosettaCM recombination protocol to remodel regions where contacts were not satisfied from the first stage and to sample full-length topologies. All models were optimized using Rosetta all-atom refinement.

Figure 2

Contact assisted predictions significantly improved over the best nonassisted predictions. The native structure is on the left, our best submitted model in the middle, and the best nonassisted prediction among all predictor groups on the right. (A) Tc734, (B) Tc684-D2, (C) Tc719-D6, (D) Tc658-D1, and (E) Tc653 (native is on top, our model is in the middle, and the best nonassisted prediction among all predictor groups is on the bottom; orthogonal views are shown on the left and right; the best nonassisted prediction has typical LRR-like curvature, which is opposite to the atypical curvature of the native).

Figure 3

Contact assisted predictions with topology-level accuracy similar to best nonassisted predictions. In each panel the native structure is on the left, our best submitted model in the middle, and the best nonassisted prediction among all predictor groups on the right. For Tc680o, since nonassisted tetramer predictions were not made, the best single chain nonassisted prediction among all predictor groups is shown. (A) Tc666, (B) Tc717-D2, (C) Tc684-D1, (D) Tc735-D2, (E) Tc673, and (F) Tc680o.

Figure 4

Contact assisted predictions are significantly improved over most nonassisted predictions based on GDT-TS scores. (A) Best BAKER contact assisted predictions versus the best nonassisted predictions among all predictor groups for the 17 target domains (the GDT-TS scores for Tc658-D1 and Tc684-D2 are close enough to appear as the same point). (B) Model 1 BAKER contact assisted predictions versus the best model 1 nonassisted predictions among all predictor groups for the 17 target domains.

Figure 5

Examples of predictions with near atomic-level accuracy. The core side chains of the submitted model (red) and native (blue) are highlighted. (A) Tc719, (B) the converged section of Tc719, (C) the symmetric homo-oligomeric tetramer, Tc680o, and (D) the interface of Tc680o.