Atomistic understanding of kinetic pathways for single base-pair binding and unbinding in DNA.
We combine free-energy calculations and molecular dynamics to elucidate a mechanism for DNA base-pair binding and unbinding in atomic detail. Specifically, transition-path sampling is used to overcome computational limitations associated with conventional techniques to harvest many trajectories for the flipping of a terminal cytosine in a 3-bp oligomer in explicit water. Comparison with free-energy projections obtained with umbrella sampling reveals four coordinates that separate true dynamic transition states from stable reactant and product states. Unbinding proceeds via two qualitatively different pathways: one in which the flipping base breaks its intramolecular hydrogen bonds before it unstacks and another in which it ruptures both sets of interactions simultaneously. Both on- and off-pathway intermediates are observed. The relation of the results to coarse-grained models for DNA-based biosensors is discussed.
Hagan
Michael F
MF
Department of Chemical Engineering, University of California, Berkeley, CA 94720, USA.
Dinner
Aaron R
AR
Chandler
David
D
Chakraborty
Arup K
AK
D020029:Base Pairing; D055592:Biophysical Phenomena; D001703:Biophysics; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D013816:Thermodynamics
D004247:DNA