Estimates of statistical significance for comparison of individual positions in multiple sequence alignments.
BACKGROUND
Profile-based analysis of multiple sequence alignments (MSA) allows for accurate comparison of protein families. Here, we address the problems of detecting statistically confident dissimilarities between (1) MSA position and a set of predicted residue frequencies, and (2) between two MSA positions. These problems are important for (i) evaluation and optimization of methods predicting residue occurrence at protein positions; (ii) detection of potentially misaligned regions in automatically produced alignments and their further refinement; and (iii) detection of sites that determine functional or structural specificity in two related families.


RESULTS
For problems (1) and (2), we propose analytical estimates of P-value and apply them to the detection of significant positional dissimilarities in various experimental situations. (a) We compare structure-based predictions of residue propensities at a protein position to the actual residue frequencies in the MSA of homologs. (b) We evaluate our method by the ability to detect erroneous position matches produced by an automatic sequence aligner. (c) We compare MSA positions that correspond to residues aligned by automatic structure aligners. (d) We compare MSA positions that are aligned by high-quality manual superposition of structures. Detected dissimilarities reveal shortcomings of the automatic methods for residue frequency prediction and alignment construction. For the high-quality structural alignments, the dissimilarities suggest sites of potential functional or structural importance.


CONCLUSIONS
The proposed computational method is of significant potential value for the analysis of protein families.
Sadreyev
Ruslan I
RI
Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center, 5323, Harry Hines Blvd, Dallas, TX 75390-9050, USA. sadreyev@chop.swmed.edu
Grishin
Nick V
NV
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000502:physiology; D019295:Computational Biology; D019143:Evolution, Molecular; D008957:Models, Genetic; D015233:Models, Statistical; D011237:Predictive Value of Tests; D011506:Proteins / Q000737:chemistry / Q000502:physiology; D016415:Sequence Alignment / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data*; D017386:Sequence Homology, Amino Acid
D000596:Amino Acids; D011506:Proteins