The pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion constituting a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with histones affects the lesion mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA-containing 64-PP within the nucleosome core particle by atomic-resolution molecular dynamics simulations and multiscale data analysis. We demonstrate that the histone core exerts important mechanical restraints that largely decrease global DNA structural fluctuations. However, the local DNA flexibility at the damaged site is enhanced due to imperfect structural adaptation to restraints imposed by the histone core. If 64-PP faces the histone core and is therefore not directly accessible by the repair protein, the complementary strand facing the solvent is deformed and exhibits higher flexibility than the corresponding strand in a naked, undamaged DNA. This may serve as an initial recognition signal for repair. Our simulations also pinpoint the structural role of proximal residues from the truncated histone tails.

Department of Informatics and Chemistry University of Chemistry and Technology Prague Technická 5 166 28 Prague Czech Republic

Institut Universitaire de France 5 rue Descartes 75005 Paris France

Université de Lorraine and CNRS LPCT UMR 7019 F 54000 Nancy France

Université de Lyon ENS de Lyon CNRS UMR 5182 Université Claude Bernard Lyon 1 Laboratoire de Chimie F69342 Lyon France

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