Overcoming sequence misalignments with weighted structural superposition.

Autor: Khazanov NA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2218, USA., Damm-Ganamet KL, Quang DX, Carlson HA
Jazyk: angličtina
Zdroj: Proteins [Proteins] 2012 Nov; Vol. 80 (11), pp. 2523-35. Date of Electronic Publication: 2012 Jul 28.
DOI: 10.1002/prot.24134
Abstrakt: An appropriate structural superposition identifies similarities and differences between homologous proteins that are not evident from sequence alignments alone. We have coupled our Gaussian-weighted RMSD (wRMSD) tool with a sequence aligner and seed extension (SE) algorithm to create a robust technique for overlaying structures and aligning sequences of homologous proteins (HwRMSD). HwRMSD overcomes errors in the initial sequence alignment that would normally propagate into a standard RMSD overlay. SE can generate a corrected sequence alignment from the improved structural superposition obtained by wRMSD. HwRMSD's robust performance and its superiority over standard RMSD are demonstrated over a range of homologous proteins. Its better overlay results in corrected sequence alignments with good agreement to HOMSTRAD. Finally, HwRMSD is compared to established structural alignment methods: FATCAT, secondary-structure matching, combinatorial extension, and Dalilite. Most methods are comparable at placing residue pairs within 2 Å, but HwRMSD places many more residue pairs within 1 Å, providing a clear advantage. Such high accuracy is essential in drug design, where small distances can have a large impact on computational predictions. This level of accuracy is also needed to correct sequence alignments in an automated fashion, especially for omics-scale analysis. HwRMSD can align homologs with low-sequence identity and large conformational differences, cases where both sequence-based and structural-based methods may fail. The HwRMSD pipeline overcomes the dependency of structural overlays on initial sequence pairing and removes the need to determine the best sequence-alignment method, substitution matrix, and gap parameters for each unique pair of homologs.
(Copyright © 2012 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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