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Physical Chemistry Chemical Physics

Structural and Dynamical instability of DNA by high occurrence of d5SICS and dNaM unnatural nucleotides

Authors: Rodrigo Galindo-Murillo; Joaquín Barroso-Flores

Publication Date: -0001-11-30  Article ASAP

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 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 d5SICS and dNaM could be useful as tools in DNA manipulation. This theoretical methodology can be used in the de novo design of UBPs.  Read more