DNA hybridization kinetics: Zippering, internal displacement and sequence dependence

Thomas E. Ouldridge, Petr Šulc, Flavio Romano, Jonathan P.K. Doye, Ard A. Louis

Research output: Contribution to journalArticlepeer-review

174 Scopus citations


Although the thermodynamics of DNA hybridization is generally well established, the kinetics of this classic transition is less well understood. Providing such understanding has new urgency because DNA nanotechnology often depends critically on binding rates. Here, we explore DNA oligomer hybridization kinetics using a coarse-grained model. Strand association proceeds through a complex set of intermediate states, with successful binding events initiated by a few metastable base-pairing interactions, followed by zippering of the remaining bonds. But despite reasonably strong interstrand interactions, initial contacts frequently dissociate because typical configurations in which they form differ from typical states of similar enthalpy in the double-stranded equilibrium ensemble. Initial contacts must be stabilized by two or three base pairs before full zippering is likely, resulting in negative effective activation enthalpies. Non-Arrhenius behavior arises because the number of base pairs required for nucleation increases with temperature. In addition, we observe two alternative pathways - pseudoknot and inchworm internal displacement - through which misaligned duplexes can rearrange to form duplexes. These pathways accelerate hybridization. Our results explain why experimentally observed association rates of GC-rich oligomers are higher than rates of AT-rich equivalents, and more generally demonstrate how association rates can be modulated by sequence choice.

Original languageEnglish (US)
Pages (from-to)8886-8895
Number of pages10
JournalNucleic acids research
Issue number19
StatePublished - Oct 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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