Revealing DNA dynamics from atomistic to genomic level by multiscale computational approaches
[eng] The study of DNA from atomistic to mesoscopic level and connecting different resolution levels constitutes a major challenge since the new millennium. In the early 2000s, experiments could resolve for the first time the structure of the nucleosome in high detail or capture physical contacts in...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/144538 |
| Acceso en línea: | https://hdl.handle.net/2445/144538 http://hdl.handle.net/10803/667845 |
| Access Level: | acceso abierto |
| Palabra clave: | ADN Cromatina Modelització multiescala DNA Chromatin Multiscale modeling |
| Sumario: | [eng] The study of DNA from atomistic to mesoscopic level and connecting different resolution levels constitutes a major challenge since the new millennium. In the early 2000s, experiments could resolve for the first time the structure of the nucleosome in high detail or capture physical contacts in the genome of segments far apart in sequence. At around the same time, the force field development for atomistic nucleic acid simulations reached a peak with parmbsc0 in 2007 and coarse grain nucleosome fiber models emerged. The first decade ended with a remarkable experimental advance in visualizing the whole genome, Hi-C. In the current decade, almost ten years after Hi-C was invented, the structure of the cell nucleus is still a very hot topic. We can now harvest the fruits of the pioneers in the first decade of multi-scale investigation of DNA and connect the different resolution levels to obtain a complete picture of DNA from electron orbitals to genome folding. In this work, we use computational approaches to dissect the different resolution levels, from atomistic MD simulations to mesoscopic secondary chromatin structure modeling. We developed a force-field (parmbsc1) for the accurate description of atomistic DNA dynamics based on quantum mechanical simulations. With the accuracy of parmbsc1, sequence-dependent effects of B-DNA flexibility beyond the base pair level were described and used as a starting point to parametrize a novel helical coarse grain model which shows similar accuracy to the DNA dynamics obtained by atomistic MD, but at much lower computational cost. In a newly developed nucleosome fiber model the coarse grain DNA algorithm is used for the linker DNA description and alongside with a simple mesoscopic characterization of the nucleosome chromatin dynamics can be probed at kilobase scale with a DNA model whose roots lie in the quantum mechanical regime. On top of that, to meet current standards of accessibility and usability of tools, the developed coarse grain DNA and nucleosome fiber model are freely available as stand-alone versions or integrated in a single webserver or large-scale online research environment platform. |
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