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Sequence dependency of canonical base pair opening in the DNA double helix
KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
2017 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, no 4, e1005463Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Public Library of Science , 2017. Vol. 13, no 4, e1005463
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-209322DOI: 10.1371/journal.pcbi.1005463ISI: 000402542900019Scopus ID: 2-s2.0-85018285834OAI: oai:DiVA.org:kth-209322DiVA: diva2:1111441
Funder
EU, European Research Council, 258980Swedish Research Council, 2015-04992Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170619

Available from: 2017-06-19 Created: 2017-06-19 Last updated: 2017-11-17Bibliographically approved
In thesis
1. Optimizing sampling of important events in complex biomolecular systems
Open this publication in new window or tab >>Optimizing sampling of important events in complex biomolecular systems
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins and DNA are large, complex molecules that carry out biological functions essential to all life. Their successful operation relies on adopting specific structures, stabilized by intra-molecular interactions between atoms. The spatial and temporal resolution required to study the mechanics of these molecules in full detail can only be obtained using computer simulations of molecular models. In a molecular dynamics simulation, a trajectory of the system is generated, which allows mapping out the states and dynamics of the molecule. However, the time and length scales characteristic of biological events are many orders of magnitude larger than the resolution needed to accurately describe the microscopic processes of the atoms. To overcome this problem, sampling methods have been developed that enhance the occurrence of rare but important events, which improves the statistics of simulation data.

This thesis summarizes my work on developing the AWH method, an algorithm that adaptively optimizes sampling toward a target function and simultaneously finds and assigns probabilities to states of the simulated system. I have adapted AWH for use in molecular dynamics simulations. In doing so, I investigated the convergence of the method as a function of its input parameters and improved the robustness of the method. I have also worked on a generally applicable approach for calculating the target function in an automatic and non-arbitrary way. Traditionally, the target is set in an ad hoc way, while now sampling can be improved by 50% or more without extra effort. I have also used AWH to improve sampling in two biologically relevant applications. In one paper, we study the opening of a DNA base pair, which due to the stability of the DNA double helix only very rarely occurs spontaneously. We show that the probability of opening depends on both nearest-neighbor and longer-range sequence effect and furthermore structurally characterize the open states. In the second application the permeability and ammonia selectivity of the membrane protein aquaporin is investigated and we show that these functions are sensitive to specific mutations.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2017. 47 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2017:72
Keyword
molecular dynamics, free energy calculation, adaptive sampling, extended ensembles, membrane proteins, DNA
National Category
Biophysics
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-217837 (URN)978-91-7729-599-0 (ISBN)
Public defence
2017-12-07, F3, Lindstedtsvägen 26, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20171117

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-11-21Bibliographically approved

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