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Theoretical study of large conformational transitions in DNA: the B<-->A conformational change in water and ethanol/water.

ABSTRACT: We explore here the possibility of determining theoretically the free energy change associated with large conformational transitions in DNA, like the solvent-induced B<-->A conformational change. We find that a combination of targeted molecular dynamics (tMD) and the weighted histogram analysis method (WHAM) can be used to trace this transition in both water and ethanol/water mixture. The pathway of the transition in the A-->B direction mirrors the B-->A pathway, and is dominated by two processes that occur somewhat independently: local changes in sugar puckering and global rearrangements (particularly twist and roll) in the structure. The B-->A transition is found to be a quasi-harmonic process, which follows closely the first spontaneous deformation mode of B-DNA, showing that a physiologically-relevant deformation is in coded in the flexibility pattern of DNA.

SUBMITTER: Noy A

PROVIDER: S-EPMC1904281 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Theoretical study of large conformational transitions in DNA: the B<-->A conformational change in water and ethanol/water.

Noy Agnes A Pérez Alberto A Laughton Charles A CA Orozco Modesto M

Nucleic acids research 20070425 10

We explore here the possibility of determining theoretically the free energy change associated with large conformational transitions in DNA, like the solvent-induced B<-->A conformational change. We find that a combination of targeted molecular dynamics (tMD) and the weighted histogram analysis method (WHAM) can be used to trace this transition in both water and ethanol/water mixture. The pathway of the transition in the A-->B direction mirrors the B-->A pathway, and is dominated by two processe ...[more]

PMID: 17459891

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Project description:X-ray free-electron laser (XFEL) is the latest generation of the X-ray source that could become an invaluable technique in structural biology. XFEL has ultrashort pulse duration, extreme peak brilliance, and high spatial coherence, which could enable the observation of the biological molecules in near nature state at room temperature without crystallization. However, for biological systems, due to their low diffraction power and complexity of sample delivery, experiments and data analysis are not straightforward, making it extremely challenging to reconstruct three-dimensional (3D) structures from single particle XFEL data. Given the current limitations to the amount and resolution of the data from such XFEL experiments, we propose a new hybrid approach for characterizing biomolecular conformational transitions by using a single 2D low-resolution XFEL diffraction pattern in combination with another known conformation. In our method, we represent the molecular structure with a coarse-grained model, the Gaussian mixture model, to describe large conformational transitions from low-resolution XFEL data. We obtain plausible 3D structural models that are consistent with the XFEL diffraction pattern by deforming an initial structural model to maximize the similarity between the target pattern and the simulated diffraction patterns from the candidate models. We tested the proposed algorithm on two biomolecules of different sizes with different complexities of conformational transitions, adenylate kinase, and elongation factor 2, using synthetic XFEL data. The results show that, with the proposed algorithm, we can successfully describe the conformational transitions by flexibly fitting the coarse-grained model of one conformation to become consistent with an XFEL diffraction pattern simulated from another conformation. In addition, we showed that the incident beam orientation has some effect on the accuracy of the 3D structure modeling and discussed the reasons for the inaccuracies for certain orientations. The proposed method could serve as an alternative approach for retrieving information on 3D conformational transitions from the XFEL diffraction patterns to interpret experimental data. Since the molecules are represented by Gaussian kernels and no atomic structure is needed in principle, such a method could also be used as a tool to seek initial models for 3D reconstruction algorithms.

Dataset Information

Theoretical study of large conformational transitions in DNA: the B<-->A conformational change in water and ethanol/water.

Publications

Theoretical study of large conformational transitions in DNA: the B<-->A conformational change in water and ethanol/water.

Similar Datasets

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