Evolutionary meandering of intermolecular interactions along the drift barrier

Significance Many cellular functions depend on highly specific intermolecular interactions, with mutational changes in each component of the interaction imposing coevolutionary pressure on the remaining members (e.g., a transcription factor and its DNA binding sites). The conflict between mutation pressure toward reduced affinity and selective pressure for greater interaction results in an evolutionary equilibrium distribution for the affinity between interacting partners. Nevertheless, conditional on the maintenance of a critical level of molecular recognition, the sites containing the key residues of binding interfaces are free to evolve. The theory developed suggests that most such evolution is a simple consequence of random genetic drift and not an outcome of adaptive fine tuning.