title: Understanding the structural and dynamic consequences of DNA epigenetic modifications: computational insights into cytosine methylation and hydroxymethylation.
abstract: We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.
authors.affiliation: a Science for Life Laboratory; Department of Cell and Molecular Biology ; Uppsala University ; Uppsala , Sweden.
authors.forename: Alexandra T P
authors.initials: AT
authors.lastname: Carvalho
authors.forename: Leonor
authors.initials: L
authors.lastname: Gouveia
authors.forename: Charan Raju
authors.initials: CR
authors.lastname: Kanna
authors.forename: Sebastian K T S
authors.initials: SK
authors.lastname: Wärmländer
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Platts
authors.forename: Shina Caroline Lynn
authors.initials: SC
authors.lastname: Kamerlin
mesh_terms: D044503:5-Methylcytosine / Q000737:chemistry / Q000378:metabolism / Q000031:analogs & derivatives; D018899:CpG Islands; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D011485:Protein Binding
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA
keywords: AFM, Atomic Force Microscopy; DDD, Dickerson-Drew Dodecamer; DFT, Density Functional Theory; DNA methylation; DNA, Deoxyribonucleic Acid; DNMT, DNA Methyltransferase; LINEs, Long Interspred Transposable Elements; MD, Molecular Dynamics; MM, Molecular Mechanics; MeCP, Methylated CpG-binding proteins; PBC, Periodic Boundary Conditions; QM, Quantum Mechanics; RDF, Radial Distribution Functions; RESP, Restrained Electrostatic Potentials Model; SINEs, Short Interspred Transposable Elements; SPME, Smooth Particle-Mesh Ewald; TET, Translocation Proteins; WT, Wild Type; epigenetics; indirect readout; molecular dynamics; recognition