Dataset Information

Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program.

ABSTRACT: Robust homology modeling to atomic-level accuracy requires in the general case successful prediction of protein loops containing small segments of secondary structure. Further, as loop prediction advances to success with larger loops, the exclusion of loops containing secondary structure becomes awkward. Here, we extend the applicability of the Protein Local Optimization Program (PLOP) to loops up to 17 residues in length that contain either helical or hairpin segments. In general, PLOP hierarchically samples conformational space and ranks candidate loops with a high-quality molecular mechanics force field. For loops identified to possess ?-helical segments, we employ an alternative dihedral library composed of (?,?) angles commonly found in helices. The alternative library is searched over a user-specified range of residues that define the helical bounds. The source of these helical bounds can be from popular secondary structure prediction software or from analysis of past loop predictions where a propensity to form a helix is observed. Due to the maturity of our energy model, the lowest energy loop across all experiments can be selected with an accuracy of sub-Ångström RMSD in 80% of cases, 1.0 to 1.5 Å RMSD in 14% of cases, and poorer than 1.5 Å RMSD in 6% of cases. The effectiveness of our current methods in predicting hairpin-containing loops is explored with hairpins up to 13 residues in length and again reaching an accuracy of sub-Ångström RMSD in 83% of cases, 1.0 to 1.5 Å RMSD in 10% of cases, and poorer than 1.5 Å RMSD in 7% of cases. Finally, we explore the effect of an imprecise surrounding environment, in which side chains, but not the backbone, are initially in perturbed geometries. In these cases, loops perturbed to 3Å RMSD from the native environment were restored to their native conformation with sub-Ångström RMSD.

SUBMITTER: Miller EB

PROVIDER: S-EPMC3694628 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program.

Miller Edward B EB Murrett Colleen S CS Zhu Kai K Zhao Suwen S Goldfeld Dahlia A DA Bylund Joseph H JH Friesner Richard A RA

Journal of chemical theory and computation 20130301 3

Robust homology modeling to atomic-level accuracy requires in the general case successful prediction of protein loops containing small segments of secondary structure. Further, as loop prediction advances to success with larger loops, the exclusion of loops containing secondary structure becomes awkward. Here, we extend the applicability of the Protein Local Optimization Program (PLOP) to loops up to 17 residues in length that contain either helical or hairpin segments. In general, PLOP hierarch ...[more]

PMID: 23814507

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Project description:BACKGROUND: When characterizing the structural topology of proteins, protein secondary structure (PSS) plays an important role in analyzing and modeling protein structures because it represents the local conformation of amino acids into regular structures. Although PSS prediction has been studied for decades, the prediction accuracy reaches a bottleneck at around 80%, and further improvement is very difficult. RESULTS: In this paper, we present an improved dictionary-based PSS prediction method called SymPred, and a meta-predictor called SymPsiPred. We adopt the concept behind natural language processing techniques and propose synonymous words to capture local sequence similarities in a group of similar proteins. A synonymous word is an n-gram pattern of amino acids that reflects the sequence variation in a protein's evolution. We generate a protein-dependent synonymous dictionary from a set of protein sequences for PSS prediction.On a large non-redundant dataset of 8,297 protein chains (DsspNr-25), the average Q3 of SymPred and SymPsiPred are 81.0% and 83.9% respectively. On the two latest independent test sets (EVA Set_1 and EVA_Set2), the average Q3 of SymPred is 78.8% and 79.2% respectively. SymPred outperforms other existing methods by 1.4% to 5.4%. We study two factors that may affect the performance of SymPred and find that it is very sensitive to the number of proteins of both known and unknown structures. This finding implies that SymPred and SymPsiPred have the potential to achieve higher accuracy as the number of protein sequences in the NCBInr and PDB databases increases. CONCLUSIONS: Our experiment results show that local similarities in protein sequences typically exhibit conserved structures, which can be used to improve the accuracy of secondary structure prediction. For the application of synonymous words, we demonstrate an example of a sequence alignment which is generated by the distribution of shared synonymous words of a pair of protein sequences. We can align the two sequences nearly perfectly which are very dissimilar at the sequence level but very similar at the structural level. The SymPred and SymPsiPred prediction servers are available at http://bio-cluster.iis.sinica.edu.tw/SymPred/.

Project description:BACKGROUND:Whenever suitable template structures are not available, usage of fragment-based protein structure prediction becomes the only practical alternative as pure ab initio techniques require massive computational resources even for very small proteins. However, inaccuracy of their energy functions and their stochastic nature imposes generation of a large number of decoys to explore adequately the solution space, limiting their usage to small proteins. Taking advantage of the uneven complexity of the sequence-structure relationship of short fragments, we adjusted the fragment insertion process by customising the number of available fragment templates according to the expected complexity of the predicted local secondary structure. Whereas the number of fragments is kept to its default value for coil regions, important and dramatic reductions are proposed for beta sheet and alpha helical regions, respectively. RESULTS:The evaluation of our fragment selection approach was conducted using an enhanced version of the popular Rosetta fragment-based protein structure prediction tool. It was modified so that the number of fragment candidates used in Rosetta could be adjusted based on the local secondary structure. Compared to Rosetta's standard predictions, our strategy delivered improved first models, +?24% and?+?6% in terms of GDT, when using 2000 and 20,000 decoys, respectively, while reducing significantly the number of fragment candidates. Furthermore, our enhanced version of Rosetta is able to deliver with 2000 decoys a performance equivalent to that produced by standard Rosetta while using 20,000 decoys. We hypothesise that, as the fragment insertion process focuses on the most challenging regions, such as coils, fewer decoys are needed to explore satisfactorily conformation spaces. CONCLUSIONS:Taking advantage of the high accuracy of sequence-based secondary structure predictions, we showed the value of that information to customise the number of candidates used during the fragment insertion process of fragment-based protein structure prediction. Experimentations conducted using standard Rosetta showed that, when using the recommended number of decoys, i.e. 20,000, our strategy produces better results. Alternatively, similar results can be achieved using only 2000 decoys. Consequently, we recommend the adoption of this strategy to either improve significantly model quality or reduce processing times by a factor 10.

Dataset Information

Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program.

Publications

Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program.

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