Compensating changes in protein multiple sequence alignments

A method was developed to identify compensating changes betweenresidues at positions in a multiple sequence alignment. (Forexample, one position might always contain a positively chargedresidue when the other is negatively charged and vice versa.)A correlation-based method was used to measure the compensationfound in the four residues at a pair of positions in any twosequences in a multiple alignment. All possible sequence pairingswere measured at the pair of positions and the resulting matrixanalysed to give a measure of cooperathity among the pairs.The basic method was sufficiently flexible to consider a numberof amino acid relatedness models based both on scalar and vectorialproperties. Pairs of compensating positions were selected bythe method and their mean separation (in a protein of knownstructure) was compared to both the mean pair-wise separationover all residues and the pairwise separation over an equivalentsample of pairs of residues selected on the basis of their conservationalone. The latter is an important control that has been omittedfrom previous studies. The results indicated that, at best,there was a slight effect (of marginal significance) leadingto the selection of closer pairs by the compensation measurewhen compared to the mean of all pairs. However, this was neveras good as the simpler measure based on conservation alone,which always found a significant majority of proteins with asample mean less than the overall mean