Molecular Modeling for a Comparative Analysis of Interactions Between 2LTRZFP and 2-LTR-Circle Junctions

In eukaryotes, one of the most often noticed DNA-binding motifs are Cys2His2 zinc finger proteins which have been extensively utilized as a framework for designing novel DNA-binding proteins. In this study, the conformational change, and binding stability, affinity and interactions of the 2LTRZFP–HIV-1 2-LTR-circle junction complexes were successfully reproduced with MD simulations, MM-PBSA/GBSA and binding mode analyses. The binding free energies were obtained, and it was found that the calculated binding free energy of Zif1 is lower than Zif2 and together with pharmacophore modeling, these binding results indicate strong affinity of 2LTRZFP for the DNA. Mutants of 2LTRZFP were analyzed. The computed energies provided proof for a relationship between the binding free energy and total electrostatic interaction energy. The mutation in a key amino acid (Glu81Tyr) of the finger 3 in position 6 showed increased binding energy to the DNA. The result agrees with our previous study which showed that the HIV-1 IN may be hindered by the 2LTRZFP. The obtained results may assist in the design of ZFPs depended on the 2-LTR-circle junctions inhibition mechanism.