Energetic and Structural Dynamic Drivers of Transcription Factors MycMax, Omomyc homodimer, and MaxMax Recognition on DNA

Basic helix–loop–helix leucine zipper (bHLHLZ) transcription factors (TFs), such as MycMax, MaxMax, and the engineered mutant Omomyc dimers, regulate gene expression by binding the E-box (5′-CACGTG-3′) motif in DNA. Here, we used microsecond molecular dynamics (MD) simulations along with MMGBSA energetic and hydrogen bonding (HB) analyses to investigate how MycMax, Omomyc, and MaxMax dimers interact with both canonical E-box and nonspecific homogeneous polyA sequences. Our MD results indicate that protein-DNA van der Waals (VDW) interactions and surface complementarity dominate the binding stability. Per-residue decomposition underscores the central role of conserved Arginine residues at the protein-DNA binding interface, while HB and information propagation or KL divergence analyses reveal a biased DNA strand association that reinforces sequence recognition for specificity. Although MaxMax binds comparatively stably the canonical E-box, it loses stability more than the other two TFs on polyA, suggesting an essential reliance of MaxMax on the E-box motif for DNA interaction coordination. MycMax exhibits moderate stability in both contexts and shows more variable dynamical responses to local DNA sequences. In contrast, Omomyc retains slightly higher binding stability than that of MycMax on Ebox and polyA DNA, suggesting an enhanced ability to sequester Myc in oncogenic settings. These findings provide new insights into dimeric bHLHLZ–TFs on DNA recognition and inform potential strategies for targeting Myc-driven transcription or overexpression in cancer.