T.I.T.O. a tool for incremental threading optimization in order to help alignment and molecular modeling at any sequence similarity level

by Labesse G. and Mornon J.-P.

G. Labesse and J.-P. Mornon, BIOINFORMATICS, 14, 206-211

This program has been developed in order to help sequence alignment when sequence identity between a query sequence and a 3D structure is low (10 to 30%). Common atom coordinates are extracted from the PDB file containing the 3D structure which is aligned in the MSF formatted file with the protein of interest. A PMF score is computed using the set of aligned sequence on the common core. This new software also assigns secondary structure elements in protein structures from the Ca trace using a procedure derived from P-SEA (Labesse G., Colloc'h N., Pothier J. and Mornon J.-P., CABIOS, vol 13., no. 3, pages 291-295). This feature gives improved creation and position of the indels. The compiled program is available for HPUX (HP) or IRIX (SGI) devices upon request at labesse@cbs.cnrs.fr

The pseudo-energy to validate the alignment is computed on the whole set of query sequences using one template. The 3D compatibility Epkb is computed as the sum of the matrices MATH[i,d] + MATH[j,d] + MATB[i,j,d]. These matrices and the side chain centroid building are mage according to Bryant S.H. and Lawrence C.E. (1993, Proteins, 16, 92-112 ).

Examples of application of sequence-structure alignments at low sequence identity (15-25%):

  • Structure modelling and site-directed mutagenesis of the rat aromatic L-amino acid pyridoxal 5'-phosphate-dependent decarboxylase: a functional study. Poupon A, Jebai F, Labesse G, Gros F, Thibault J, Mornon JP, Krieger M Proteins (1999) 37 191-203.
  • Characterization and molecular cloning of an adenosine kinase from Babesia canis rossi. Carret C, Delbecq S, Labesse G, Carcy B, Precigout E, Moubri K, Schetters TP, Gorenflot A Eur. J. Biochem. (1999) 265 1015-21.
  • Engineering, expression and biochemical characterization of the hemoglobin domain of a flavohemoprotein from Erwinia chrysanthemi G. Labesse, Craescu C.T., Mispelter J., Chottard G., Marden M.C., Pin S., Forest E., J.-P. Mornon and M. Boccara. Eur. J. Biochem. (1998) 253, 751-759.
  • HAH1 is a copper binding protein with distinct amino acid residues mediating copper homeostasis and antioxidant defense. I. H. Hung, R. L. B. Casareno, G. Labesse, F. S. Mathews and J. D. Gitlin. J. Biol. Chem. (1998) 273, 1749-1754.
  • CMP kinase from Escherichia coli is structurally related to other nucleoside monophosphate kinases. N. Bucurenci, H. Sakamoto, P. Briozzo, N. Palibroda, L. Serina, R. S. Sarfati, G. Labesse, G. Briand, A. Danchin, O. Barzu and A.-M. Gilles. J. Biol. Chem. (1996) 271, 2856-62