DNA hybridization kinetics: Zippering, internal displacement and sequence dependence

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

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

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
Volume41
Issue number19
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Fingerprint

Base Pairing
DNA
Nanotechnology
Thermodynamics
Temperature

ASJC Scopus subject areas

  • Genetics

Cite this

DNA hybridization kinetics : Zippering, internal displacement and sequence dependence. / Ouldridge, Thomas E.; Sulc, Petr; Romano, Flavio; Doye, Jonathan P.K.; Louis, Ard A.

In: Nucleic Acids Research, Vol. 41, No. 19, 01.10.2013, p. 8886-8895.

Research output: Contribution to journalArticle

Ouldridge, Thomas E. ; Sulc, Petr ; Romano, Flavio ; Doye, Jonathan P.K. ; Louis, Ard A. / DNA hybridization kinetics : Zippering, internal displacement and sequence dependence. In: Nucleic Acids Research. 2013 ; Vol. 41, No. 19. pp. 8886-8895.
@article{ebafbf61d55d47e0bea374283fdf0cb7,
title = "DNA hybridization kinetics: Zippering, internal displacement and sequence dependence",
abstract = "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.",
author = "Ouldridge, {Thomas E.} and Petr Sulc and Flavio Romano and Doye, {Jonathan P.K.} and Louis, {Ard A.}",
year = "2013",
month = "10",
day = "1",
doi = "10.1093/nar/gkt687",
language = "English (US)",
volume = "41",
pages = "8886--8895",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "19",

}

TY - JOUR

T1 - DNA hybridization kinetics

T2 - Zippering, internal displacement and sequence dependence

AU - Ouldridge, Thomas E.

AU - Sulc, Petr

AU - Romano, Flavio

AU - Doye, Jonathan P.K.

AU - Louis, Ard A.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84886016409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886016409&partnerID=8YFLogxK

U2 - 10.1093/nar/gkt687

DO - 10.1093/nar/gkt687

M3 - Article

C2 - 23935069

AN - SCOPUS:84886016409

VL - 41

SP - 8886

EP - 8895

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 19

ER -