Exploring the effects of mutations on NFAT5-DNA binding using molecular dynamics simulations and energy calculations

NFAT5, an activated T-cell factor, plays a regulatory role in a variety of autoimmune processes through specific recognition with DNA. However, the details of the interaction of NFAT5 with DNA are unclear. Focused on the complexes of wild type (WT) and mutant NFAT5 with DNA complexes, respectively, we have conducted research on the conformational and dynamics effects caused by residue mutations through molecular dynamics (MD) simulations combined with MM-PBSA prediction. According to the results of MM-PBSA, non-polar interactions are the main driving force in the interaction between NFAT5 and DNA. At the same time, 26 residues play a key role in the interaction with DNA. The energy decomposition results suggest that extensive interactions between the nitrogenous bases of DNA and NFAT5 are responsible for the specific recognition of DNA by NFAT5. By superimposing the structures of mutants and WT complexes, it was found that mutations not only affect the mutated residues, but also change the binding contribution of other amino acids, hydrogen bonding interactions and the stability of the complexes. These results provide a strong rationale and new ideas for NFAT5 as a new target for the treatment of autoimmune diseases.