CORRELATED MUTATIONS CONTAIN INFORMATION ABOUT PROTEIN-PROTEIN INTERACTION

Many proteins have evolved to form specific molecular complexes and th e specificity of this interaction is essential for their function. The network of the necessary inter-residue contacts must consequently con strain the protein sequences to some extent. Ln other words, the seque nce of an interacting protein must reflect the consequence of this pro cess of adaptation. It is reasonable to assume that the sequence chang es accumulated during the evolution of one of the interacting proteins must be compensated by changes in the other. Here we apply a method f or detecting correlated changes in multiple sequence alignments to a s et of interacting protein domains and show that positions where change s occur in a correlated fashion in the two interacting molecules tend to be close to the protein-protein interfaces. This leads to the possi bility of developing a method for predicting contacting pairs of resid ues from the sequence alone. Such a method would not need the knowledg e of the structure of the interacting proteins, and hence would be bot h radically different and more widely applicable than traditional dock ing methods. We indeed demonstrate here that the information about cor related sequence changes is sufficient to single out the right inter-d omain docking solution amongst many wrong alternatives of two-domain p roteins. The same approach is also used here in one case (haemoglobin) where we attempt to predict the interface of two different proteins r ather than two protein domains. Finally, we report here a prediction a bout the inter-domain contact regions of the heat-shock protein Hsc70 based only on sequence information. (C) 1997 Academic Press Limited.