DNA hybridization kinetics: zippering, internal displacement and sequence dependence.
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.
Rudolf Peierls Centre for Theoretical Physics, Department of Physics, University of Oxford, 1 Keble Road, OX1 3NP, Oxford, UK and Physical & Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, OX1 3QZ, Oxford, UK.
Thomas E
TE
Ouldridge
Petr
P
Sulc
Flavio
F
Romano
Jonathan P K
JP
Doye
Ard A
AA
Louis
D020029:Base Pairing; D001483:Base Sequence; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D009693:Nucleic Acid Hybridization; D012091:Repetitive Sequences, Nucleic Acid; D013816:Thermodynamics
D004247:DNA