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Advanced multiscale simulation of DNA

Final Report Summary - SIMDNA (Advanced multiscale simulation of DNA)

Our long-term objective is to develop a continuum of theoretical methodologies able to represent DNA at all levels of resolutions navigating across different time and space scales. The ERC grant has helped us to make important progress in developing such a continuum of methodologies, from QM to macroscopic simulation methods. As a major output of our work we have opened to the community our parmbsc1 force-field for DNA simulation which has become the “gold standard” in the field and have advanced in the use of QM/MM approaches to deal with DNA. We have developed mesoscopic technologies that allowed us to easily represent naked DNAs with 102-103 base pairs, and similar methods to reproduce nucleosome strings with hundreds of nucleosomes, and we expect during 2017 to simulate entire yeast chromosomes incorporating both MNAseq and HiC restrictions. All methods developed have been incorporated in public accessible tools that are now distributed under the H2020 MuG project. The ERC grant allowed us to create an experimental laboratory, which has been used to validate our theoretical simulations and to derive high quality nucleosomal maps, and in the last years HiC data which can be incorporated into our physical models of chromatin. Thanks to the possibility to obtain our own experimental information, we are now investigating complex aspects such as the inter-relationship between protein-binding and nucleosome organization, global chromatin changes related to stress situation or cell cycle evolution. We have also made important advances in fundamental aspects of DNA such as: sequence dependent physical properties, impact of mismatches, effect of epigenetic changes, mechanisms of DNA allosterism, models of protein-DNA, recognition, mechanisms of enzymatic DNA cleavage, etc. Finally, our ERC project allowed us to explore new ways to characterize the way in which dynamic information is transferred in macromolecules. The resulting methods are applicable not only to nucleic acids, but also to proteins, and have provided new clues on the mechanism of reaction of enzymes, and on the basic mechanisms of signal transfer and allosterism in biomacromolecules.