Bioinformatics Vol. 17 no. 8 2001
Pages 700-712
© 2001 Oxford University Press
AL2CO: calculation of positional conservation in a protein sequence alignment
1 Howard Hughes Medical Institute
2 Department of Biochemistry, University of
Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas,
TX 75390-9050, USA
Received on September 12, 2000
; revised on February 23, 2001
; accepted on February 28, 2001
Motivation: Amino acid sequence alignments are widely used in the analysis of protein structure, function and evolutionary relationships. Proteins within a superfamily usually share the same fold and possess related functions. These structural and functional constraints are reflected in the alignment conservation patterns. Positions of functional and/or structural importance tend to be more conserved. Conserved positions are usually clustered in distinct motifs surrounded by sequence segments of low conservation. Poorly conserved regions might also arise from the imperfections in multiple alignment algorithms and thus indicate possible alignment errors. Quantification of conservation by attributing a conservation index to each aligned position makes motif detection more convenient. Mapping these conservation indices onto a protein spatial structure helps to visualize spatial conservation features of the molecule and to predict functionally and/or structurally important sites. Analysis of conservation indices could be a useful tool in detection of potentially misaligned regions and will aid in improvement of multiple alignments.
Results: We developed a program to calculate a conservation index
at each position in a multiple sequence alignment using several
methods. Namely, amino acid frequencies at each position are
estimated and the conservation index is calculated from these
frequencies. We utilize both unweighted frequencies and frequencies
weighted using two different strategies. Three conceptually
different approaches (entropy-based, variance-based and matrix
score-based) are implemented in the algorithm to define the
conservation index. Calculating conservation indices for 35522
positions in 284 alignments from SMART database we demonstrate that
different methods result in highly correlated (correlation
coefficient more than 0.85) conservation indices. Conservation
indices show statistically significant correlation between
sequentially adjacent positions 
and 
, where 
, and averaging of the indices over the window of three
positions is optimal for motif detection. Positions with gaps
display substantially lower conservation properties. We compare
conservation properties of the SMART alignments or FSSP structural
alignments to those of the ClustalW alignments. The results suggest
that conservation indices should be a valuable tool of alignment
quality assessment and might be used as an objective function for
refinement of multiple alignments.
Availability: The C code of the AL2CO program and its pre-compiled versions for several platforms as well as the details of the analysis are freely available at ftp://iole.swmed.edu/pub/al2co/.
Contact: grishin{at}chop.swmed.edu
* To whom correspondence should be addressed.
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