Evolutionary inaccuracy of pairwise structural alignments

Sadowski, Michael I.; Taylor, William R.

doi:10.1093/bioinformatics/bts103

Cited by 15 publications

(19 citation statements)

References 47 publications

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“…Additionally, the alignment algorithms report different scores as measures of similarity. To circumvent these limitations, structural similarity was assessed using a generic metric-fTM score (24). Significant correlation was observed between the fTM score and RMSD for both datasets (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Consequences of domain insertion on sequence-structure divergence in a superfold

Pandya

Brown

Šali

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Although the universe of protein structures is vast, these innumerable structures can be categorized into a finite number of folds. New functions commonly evolve by elaboration of existing scaffolds, for example, via domain insertions. Thus, understanding structural diversity of a protein fold evolving via domain insertions is a fundamental challenge. The haloalkanoic dehalogenase superfamily serves as an excellent model system wherein a variable cap domain accessorizes the ubiquitous Rossmann-fold core domain. Here, we determine the impact of the cap-domain insertion on the sequence and structure divergence of the core domain. Through quantitative analysis on a unique dataset of 154 core-domain-only and capdomain-only structures, basic principles of their evolution have been uncovered. The relationship between sequence and structure divergence of the core domain is shown to be monotonic and independent of the corresponding type of domain insert, reflecting the robustness of the Rossmann fold to mutation. However, core domains with the same cap type share greater similarity at the sequence and structure levels, suggesting interplay between the cap and core domains. Notably, results reveal that the variance in structure maps to α-helices flanking the central β-sheet and not to the domain-domain interface. Collectively, these results hint at intramolecular coevolution where the fold diverges differentially in the context of an accessory domain, a feature that might also apply to other multidomain superfamilies. directed evolution | phosphoryl transferase | protein evolution | structural bioinformatics | HAD superfamily T he universe of protein structures is vast and diverse, yet these innumerable structures can be categorized into a finite number of folds (1). Ideally, the protein fold has a robust yet evolvable architecture to deliver chemistry, bind interaction partners, or provide scaffolding. A popular strategy for the acquisition of new function(s) is the topological alteration of the fold to provide a new evolutionary platform. More frequently, existing and stable scaffolds are elaborated to attain diversity that is due to accumulation of stochastic, independent, and near-neutral mutations in the protein sequence. In a large number of cases, the expansion of functional space has been achieved by the tandem fusion of two or three domains to form evolutionary modules known as supradomains (2). An analysis of catalytic domains fused to the nucleotide-binding Rossmann domain has revealed that the sequential order of their connections is conserved because each pairing arose from a single recombination event (3). Another common structural embellishment is that of domain insertion(s) into existing folds (4)-a strategy that is ubiquitous in all structural classes, i.e., all α, all β, α + β, and α/β (5). For example, members of the A, B, and Y DNA polymerase superfamilies, Rab geranylgeranyl transferase superfamily, and alcohol dehydrogenase superfamily have inserted different domains into the native fold to fine tun...

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Section: Resultsmentioning

confidence: 99%

Consequences of domain insertion on sequence-structure divergence in a superfold

Pandya

Brown

Šali

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The objective comparative evaluation of protein structure aligner performance is problematic due to the lack of standardized geometric methods, and accuracy is often assessed relative to manually curated sequence alignments . The underlying difficulty stems from the functional dependence of the RMSD on the number of aligned residue positions considered.…”

Section: Resultsmentioning

confidence: 99%

“…Proposed methods differ widely in terms of the dimensionality used to represent the protein residue string, the scoring (objective) function for structural similarity, and the heuristic algorithm used to optimise the objective function. Recent studies of comparative performance highlight a continued need to improve the geometric quality and consistency of computed structural alignments. The principal difficulties concern the accommodation of natural structural variation and plasticity in protein alignment, complicated by a need for fully concordant measures of structural similarity.…”

Section: Introductionmentioning

confidence: 99%

“…Since protein structure is kept intact, unbent flexible alignments may be legitimately compared directly with those generated by rigid‐body methods . Notwithstanding the advantages afforded by flexible aligners in accounting for large conformational change, the introduction of flexibility inevitably enlarges the space that must be searched compared with rigid‐body methods, and this can compromise alignment quality . In a recent study of achievable alignment quality, defined by intuitive measures based on the largest number of residue positions that can be superimposed within predefined distance limits, it was concluded that rigid‐body aligners are capable of delivering the same levels of accuracy as flexible aligners …”

Section: Introductionmentioning

confidence: 99%

“…47 Notwithstanding the advantages afforded by flexible aligners in accounting for large conformational change, the introduction of flexibility inevitably enlarges the space that must be searched compared with rigid-body methods, and this can compromise alignment quality. 35 In a recent study of achievable alignment quality, defined by intuitive measures based on the largest number of residue positions that can be superimposed within predefined distance limits, it was concluded that rigid-body aligners are capable of delivering the same levels of accuracy as flexible aligners. 71 Here, we describe POLYFIT, a rigid-body algorithm for automated pairwise and multiple protein structural alignment based on Smith-Waterman local alignment to establish a robust set of initial positions.…”

Section: Introductionmentioning

confidence: 99%

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Adaptive Smith-Waterman residue match seeding for protein structural alignment

et al. 2013

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The POLYFIT rigid-body algorithm for automated global pairwise and multiple protein structural alignment is presented. Smith-Waterman local alignment is used to establish a set of seed equivalences that are extended using Needleman-Wunsch dynamic programming techniques. Structural and functional interaction constraints provided by evolution are encoded as one-dimensional residue physical environment strings for alignment of highly structurally overlapped protein pairs. Local structure alignment of more distantly related pairs is carried out using rigid-body conformational matching of 15-residue fragments, with allowance made for less stringent conformational matching of metal-ion and small molecule ligand-contact, disulphide bridge, and cis-peptide correspondences. Protein structural plasticity is accommodated through the stepped adjustment of a single empirical distance parameter value in the calculation of the Smith-Waterman dynamic programming matrix. Structural overlap is used both as a measure of similarity and to assess alignment quality. Pairwise alignment accuracy has been benchmarked against that of 10 widely used aligners on the Sippl and Wiederstein set of difficult pairwise structure alignment problems, and more extensively against that of Matt, SALIGN, and MUSTANG in pairwise and multiple structural alignments of protein domains with low shared sequence identity in the SCOP-ASTRAL 40% compendium. The results demonstrate the advantages of POLYFIT over other aligners in the efficient and robust identification of matching seed residue positions in distantly related protein targets and in the generation of longer structurally overlapped alignment lengths. Superposition-based application areas include comparative modeling and protein and ligand design. POLYFIT is available on the Web server at http://polyfit.insa-toulouse.fr.

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Structure alignment of membrane proteins: Accuracy of available tools and a consensus strategy

Stamm

Forrest

2015

Proteins

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Protein structure alignment methods are used for the detection of evolutionary and functionally related positions in proteins. A wide array of different methods are available, but the choice of the best method is often not apparent to the user. Several studies have assessed the alignment accuracy and consistency of structure alignment methods, but none of these explicitly considered membrane proteins, which are important targets for drug development and have distinct structural features. Here, we compared 13 widely-used pairwise structural alignment methods on a test set of homologous membrane protein structures (called HOMEP3). Each pair of structures was aligned and the corresponding sequence alignment was used to construct homology models. The model accuracy compared to the known structures was assessed using scoring functions not incorporated in the tested structural alignment methods. The analysis shows that fragment-based approaches such as FR-TM-align are the most useful for aligning structures of membrane proteins. Moreover, fragment-based approaches are more suitable for comparison of protein structures that have undergone large conformational changes. Nevertheless, no method was clearly superior to all other methods. Additionally, all methods lack a measure to rate the reliability of a position within a structure alignment. To solve both of these problems, we propose a consensus-type approach, combining alignments from four different methods, namely FR-TM-align, DaliLite, MATT and FATCAT. Agreement between the methods is used to assign confidence values to each position of the alignment. Overall, we conclude that there remains scope for the improvement of structural alignment methods for membrane proteins.

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Evolutionary inaccuracy of pairwise structural alignments

Cited by 15 publications

References 47 publications

Consequences of domain insertion on sequence-structure divergence in a superfold

Consequences of domain insertion on sequence-structure divergence in a superfold

Adaptive Smith-Waterman residue match seeding for protein structural alignment

Structure alignment of membrane proteins: Accuracy of available tools and a consensus strategy

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