Evolutionary meandering of intermolecular interactions along the drift barrier

Michael Lynch, Kyle Hagner

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Many cellular functions depend on highly specific intermolecular interactions, for example transcription factors and their DNA binding sites, microRNAs and their RNA binding sites, the interfaces between heterodimeric protein molecules, the stems in RNA molecules, and kinases and their response regulators in signal-transduction systems. Despite the need for complementarity between interacting partners, such pairwise systems seem to be capable of high levels of evolutionary divergence, even when subject to strong selection. Such behavior is a consequence of the diminishing advantages of increasing binding affinity between partners, the multiplicity of evolutionary pathways between selectively equivalent alternatives, and the stochastic nature of evolutionary processes. Because mutation pressure toward reduced affinity conflicts with selective pressure for greater interaction, situations can arise in which the expected distribution of the degree of matching between interacting partners is bimodal, even in the face of constant selection. Although biomolecules with larger numbers of interacting partners are subject to increased levels of evolutionary conservation, their more numerous partners need not converge on a single sequence motif or be increasingly constrained in more complex systems. These results suggest that most phylogenetic differences in the sequences of binding interfaces are not the result of adaptive fine tuning but a simple consequence of random genetic drift.

Original languageEnglish (US)
Pages (from-to)E30-E38
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - Jan 6 2015
Externally publishedYes


  • Cellular evolution
  • Coevolution
  • Molecular interaction
  • Random genetic drift
  • Transcription

ASJC Scopus subject areas

  • General


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