Atomistic Understanding of Kinetic Pathways for Single Base-Pair Binding and Unbinding in DNA

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 24; pp. 13922 - 13927
• Main Authors: Hagan, Michael F., Dinner, Aaron R., Chandler, David, Chakraborty, Arup K.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25-11-2003; National Acad Sciences
• Subjects: Atomic interactions; Base Pairing; Biological Sciences; Biophysical Phenomena; Biophysics; Coordinate systems; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - metabolism; Free energy; Hydrogen Bonding; Hydrogen bonds; Kinetics; Models, Molecular; molecular dynamics; Nucleic Acid Conformation; Nucleic acids; Oligomers; Solvents; Thermodynamics; Trajectories
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2036378100

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.