We present detailed computational analyses of the binding of four dinucleotides to a highly sequence-selective single-stranded DNA (ssDNA) binding antibody (ED-10) and selected point mutants. Anti-DNA antibodies are central to the pathogenesis of systemic lupus erythematosus (SLE), and a more complete understanding of the mode of binding of DNA and other ligands will be necessary to elucidate the role of anti-DNA antibodies in the kidney inflammation associated with SLE. Classical molecular mechanics based molecular dynamics simulations and density functional theory (DFT) computations were applied to pinpoint the origin of selectivity for the 5′-nucleotide. In particular, the strength of interactions between each nucleotide and the surrounding residues were computed using MMGBSA as well as DFT applied to a cluster model of the binding site. The results agree qualitatively with experimental binding free energies, and indicate that π-stacking, CH/π, NH/π, and hydrogen-bonding interactions all contribute to 5′-base selectivity in ED-10. Most importantly, the selectivity for dTdC over dAdC arises primarily from differences in the strength of π-stacking and XH/π interactions with the surrounding aromatic residues; hydrogen bonds play little role. These data suggest that a key Tyr residue, which is not present in other anti-DNA antibodies, plays a key role in the 5′-base selectivity, while we predict that the mutation of a single Trp residue can tune the selectivity for dTdC over dAdC.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Materials Chemistry
- Surfaces, Coatings and Films