Saturating representation of loop conformational fragments in structure databanks

Narcis Fernandez-Fuentes,András Fiser

doi:10.1186/1472-6807-6-15

Narcis Fernandez-Fuentes, András Fiser

Open Access

https://doi.org/10.1186/1472-6807-6-15

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Abstract

BackgroundShort fragments of proteins are fundamental starting points in various structure prediction applications, such as in fragment based loop modeling methods but also in various full structure build-up procedures. The applicability and performance of these approaches depend on the availability of short fragments in structure databanks.ResultsWe studied the representation of protein loop fragments up to 14 residues in length. All possible query fragments found in sequence databases (Sequence Space) were clustered and cross referenced with available structural fragments in Protein Data Bank (Structure Space). We found that the expansion of PDB in the last few years resulted in a dense coverage of loop conformational fragments. For each loops of length 8 in the current Sequence Space there is at least one loop in Structure Space with 50% or higher sequence identity. By correlating sequence and structure clusters of loops we found that a 50% sequence identity generally guarantees structural similarity. These percentages of coverage at 50% sequence cutoff drop to 96, 94, 68, 53, 33 and 13% for loops of length 9, 10, 11, 12, 13, and 14, respectively. There is not a single loop in the current Sequence Space at any length up to 14 residues that is not matched with a conformational segment that shares at least 20% sequence identity. This minimum observed identity is 40% for loops of 12 residues or shorter and is as high as 50% for 10 residue or shorter loops. We also assessed the impact of rapidly growing sequence databanks on the estimated number of new loop conformations and found that while the number of sequentially unique sequence segments increased about six folds during the last five years there are almost no unique conformational segments among these up to 12 residues long fragments.ConclusionThe results suggest that fragment based prediction approaches are not limited any more by the completeness of fragments in databanks but rather by the effective scoring and search algorithms to locate them. The current favorable coverage and trends observed will be further accentuated with the progress of Protein Structure Initiative that targets new protein folds and ultimately aims at providing an exhaustive coverage of the structure space.

Highlights

Short fragments of proteins are fundamental starting points in various structure prediction applications, such as in fragment based loop modeling methods and in various full structure build-up procedures
The first ones are the template based approaches that have been employed in the Protein Structure Initiative (PSI)[6]
We explore the question of what fraction of loops extracted from all known protein sequences (Sequence Space) is covered by loops extracted form all known protein structures (Structure Space)

Summary

Introduction

Short fragments of proteins are fundamental starting points in various structure prediction applications, such as in fragment based loop modeling methods and in various full structure build-up procedures. Some of the most accurate methods available assemble full protein structures by locating short segments in the databanks and packing them together using some sort of minimization protocol such as Monte Carlo simulation[8,9]. These approaches proved to be useful to provide reasonable structures (within 4–8 A RMSD to the experimental solution) for small proteins, typically less than a 100 residues[10]. To improve the accuracy of models that are already subject to computational modeling and to extend the applicability of whole structure buildup methods to more sequences it is critical to have a good selection of short building blocks in the structure databases

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