Journal Article

Variable gap penalty for protein sequence–structure alignment

M.S. Madhusudhan, Marc A. Marti-Renom, Roberto Sanchez and Andrej Sali

in Protein Engineering, Design and Selection

Volume 19, issue 3, pages 129-133
Published in print March 2006 | ISSN: 1741-0126
Published online January 2006 | e-ISSN: 1741-0134 | DOI: http://dx.doi.org/10.1093/protein/gzj005
Variable gap penalty for protein sequence–structure alignment

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The penalty for inserting gaps into an alignment between two protein sequences is a major determinant of the alignment accuracy. Here, we present an algorithm for finding a globally optimal alignment by dynamic programming that can use a variable gap penalty (VGP) function of any form. We also describe a specific function that depends on the structural context of an insertion or deletion. It penalizes gaps that are introduced within regions of regular secondary structure, buried regions, straight segments and also between two spatially distant residues. The parameters of the penalty function were optimized on a set of 240 sequence pairs of known structure, spanning the sequence identity range of 20–40%. We then tested the algorithm on another set of 238 sequence pairs of known structures. The use of the VGP function increases the number of correctly aligned residues from 81.0 to 84.5% in comparison with the optimized affine gap penalty function; this difference is statistically significant according to Student's t-test. We estimate that the new algorithm allows us to produce comparative models with an additional ∼7 million accurately modeled residues in the ∼1.1 million proteins that are detectably related to a known structure.

Keywords: comparative protein structure modeling; gap penalty function; homology modeling; sequence–structure alignment

Journal Article.  3486 words.  Illustrated.

Subjects: Proteins

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