Structure and singly occupied molecular orbital analysis of anionic tautomers of guanine

Recently we reported the discovery of adiabatically bound anions of guanine which might be involved in the processes of DNA damage by low-energy electrons and in charge transfer through DNA. These anions correspond to some tautomers that have been ignored thus far. They were identified using a hybrid quantum mechanical-combinatorial approach in which an energy-based screening was performed on the library of 499 tautomers with their relative energies calculated with quantum chemistry methods. In the current study we analyze the adiabatically bound anions of guanine in two aspects: 1) the geometries and excess electron distributions are analyzed and compared with anions of the most stable neutrals to identify the sources of stability; 2) the chemical space of guanine tautomers is explored to verify if these new tautomers are contained in a particular subspace of the tautomeric space. The first task involves the development of novel approaches – the quantum chemical data like electron density, orbital and information on its bonding/antibonding character are coded into holograms and analyzed using chemoinformatics techniques. The second task is completed using substructure analysis and clustering techniques performed on molecules represented by 2D fingerprints. The major conclusion is that the high stability of adiabatically bound anions originates from the bonding character of the pi orbital occupied by the excess electron. This compensates for the antibonding character that usually causes significant buckling of the ring. Also the excess electron is more homogenously distributed over both rings than in the case of anions of the most stable neutral species. In terms of 2D substructure, the most stable anionic tautomers generally have additional hydrogen atoms at C8 and/or C2 and they don’t have hydrogen atoms attached to C4, C5 and C6. They also form an “island of stability” in the tautomeric space of guanine

Predicting the effects of basepair mutations in DNA-protein complexes by thermodynamic integration

AbstractThermodynamically rigorous free energy methods in principle allow the exact computation of binding free energies in biological systems. Here, we use thermodynamic integration together with molecular dynamics simulations of a DNA-protein complex to compute relative binding free energies of a series of mutants of a protein-binding DNA operator sequence. A guanine-cytosine basepair that interacts strongly with the DNA-binding protein is mutated into adenine-thymine, cytosine-guanine, and thymine-adenine. It is shown that basepair mutations can be performed using a conservative protocol that gives error estimates of ∼10% of the change in free energy of binding. Despite the high CPU-time requirements, this work opens the exciting opportunity of being able to perform basepair scans to investigate protein-DNA binding specificity in great detail computationally

Complete Reaction Studies in Exobiology - the Chemistry and Photochemistry of Nucleic Acid Constituents and Related Compounds, and Their Detection, Characterization, and Isolation Semiannual Progress Report No. 4 /final/

Fluorescence spectra for purines, guanine, and benzimidazole - photolysis and photochemical reactions of nucleotide derivatives and isolation of their photolytic primary product