Computational Insights into the Differentiated Binding Affinities of Myc, Max, and Omomyc Dimers to the E-boxes of DNA

Myc is a bHLHZip protein involved in growth control and cancer, which does not form a homodimer. Myc operates in a network with its heterodimerization partner Max, the latter of which can form homodimer and heterodimer. Omomyc, a polypeptide, can block Myc to treat cancers because it can both homodimerize as efficiently as Max and heterodimerize with both Myc and Max. However, the binding efficiencies to DNA for the mentioned two homodimers (Omomyc-Omomyc and Max-Max) and three heterodimers (Myc-Max, Omomyc-Myc, and Omomyc-Max) are still controversial. By molecular dynamics simulations and MM/GBSA free energy calculation, we ranked the binding affinities of five dimers to DNA and analyzed the contribution of single amino acids to the molecular recognition of dimers to DNA. Our simulation showed that the Omomyc-Omomyc dimer exhibited the highest binding energy to DNA, followed by the Omomyc-Myc, Max-Max, Omomyc-Max, and Myc-Max dimers. Moreover, five Arg residues (i.e., 7, 8, 15, 17, and 18 numbered by Omomyc) and five Lys residues (i.e., 6, 22, 40, 43, and 48 numbered by Omomyc) dominated the binding of various dimers to DNA while the residues Asp23 and Asp37 weakened the affinities via repulsive interaction. Our simulation would provide worthy information for further development of the structure-based design of novel Omomyc-like peptide inhibitors against Myc in the future.