How possible is the detection of correlated mutations?

The remarkable conservation of protein structure, compared to that of seque nces, suggests that, in the course of evolution, residue substitutions whic h tend to destabilise a particular structure must be compensated by other s ubstitutions that confer greater stability on that structure. Given the com pactness of proteins, spatially close residues are expected to undergo the compensatory process. Surprisingly, approaches designed to detect such corr elated changes have led, until now, only to limited success in detecting pa irs of residues adjacent in the three-dimensional structures. We have under taken, by simulating the evolution of DNA sequences including sites mutatin g in a correlated manner, to analyse whether such poor results can be attri buted to the detection methods or if this failure could result from a compe nsatory process more complex than that implicitly underlying the different approaches. Present results show that only methods taking into account the phylogenetic reconstruction can lead to correct detection.