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About the Authors:
Viveca Lindahl
Affiliations Department of Physics and Swedish e-Science Research Center, KTH Royal Institute of Technology, Stockholm, Sweden, Science for Life Laboratory, Stockholm and Uppsala, Stockholm, Sweden
ORCID http://orcid.org/0000-0002-2679-3235
Alessandra Villa
Affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
Berk Hess
* E-mail: [email protected]
Affiliations Department of Physics and Swedish e-Science Research Center, KTH Royal Institute of Technology, Stockholm, Sweden, Science for Life Laboratory, Stockholm and Uppsala, Stockholm, Sweden
ORCID http://orcid.org/0000-0002-7498-7763Abstract
The flipping-out of a DNA base from the double helical structure is a key step of many cellular processes, such as DNA replication, modification and repair. Base pair opening is the first step of base flipping and the exact mechanism is still not well understood. We investigate sequence effects on base pair opening using extensive classical molecular dynamics simulations targeting the opening of 11 different canonical base pairs in two DNA sequences. Two popular biomolecular force fields are applied. To enhance sampling and calculate free energies, we bias the simulation along a simple distance coordinate using a newly developed adaptive sampling algorithm. The simulation is guided back and forth along the coordinate, allowing for multiple opening pathways. We compare the calculated free energies with those from an NMR study and check assumptions of the model used for interpreting the NMR data. Our results further show that the neighboring sequence is an important factor for the opening free energy, but also indicates that other sequence effects may play a role. All base pairs are observed to have a propensity for opening toward the major groove. The preferred opening base is cytosine for GC base pairs, while for AT there is sequence dependent competition between the two bases. For AT opening, we identify two non-canonical base pair interactions contributing to a local minimum in the free energy profile. For both AT and CG we observe long-lived interactions with water and with sodium ions at specific sites on the open base pair.
Author summary
The DNA double helix, a molecule that stores biological information, has become an iconic image of biomedical research. In order to use or repair the information it carries, the bases that are stacked in the helix need to be chemically exposed. This can happen either by separating the...