title: Structural and dynamical instability of DNA caused by high occurrence of d5SICS and dNaM unnatural nucleotides.
abstract: In vivo inclusion of unnatural base pairs (UBPs) into functional DNA was recently reported for compounds 2,6-dimethyl-2H-isoquiniline-1-thione (d5SICS, X) and 2-methoxy-3-methylnaphthalene (dNaM, Y) in a modified E. coli strand, for which high-fidelity replication was observed. Yet, little is known about possible genetic consequences they have in largely substituted DNA. Using a converged microsecond long molecular dynamics (MD) simulation of the sequences 5'-GCGCAAXTTGCGC-3' and 5'-GCGCXAXTXGCGC-3', where X represents the UBP, we show that in the system with only a single XY UBP pair present, the global RMS deviation from canonical B-DNA in our control simulations is ∼3 Å and a fully converged ensemble is achieved within 2 µs. With three UBPs, deviation increases to ∼5 Å and convergence is not achieved within 10 µs of sampling time. With five UBPs, no convergence is observed and the double helix collapses into a globular structure. A fully optimized structure of the trimer d(GXC) was obtained using the density functional theory method B97D/cc-pVTZ and resulted in an RMSD value of ∼2 Å when compared to the most populated structure obtained from the MD simulations. Their calculated interaction energy is -3.7 kcal mol-1. It is thus unlikely that d5SICS and dNaM could be useful as tools in DNA manipulation. This theoretical methodology can be used in the de novo design of UBPs.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 2000 East 30 South Skaggs 201, Salt Lake City, Utah 84112, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Galindo-Murillo
authors.forename: Joaquín
authors.initials: J
authors.lastname: Barroso-Flores
mesh_terms: D020029:Base Pairing; D001483:Base Sequence; D059371:DNA, B-Form / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D007546:Isoquinolines / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009281:Naphthalenes / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000737:chemistry*
chemical_list: D059371:DNA, B-Form; D007546:Isoquinolines; D009281:Naphthalenes; D009711:Nucleotides; C031721:naphthalene; C039109:isoquinoline