MD investigation on the binding of microphthalmia-associated transcription factor with DNA

Abstract

As a main regulator of melanocyte development and an key melanoma oncogene, microphthalmia-associated transcription factor (MITF) is one of the proteins in the basic helix-loop-helix zipper (bHLHZip) transcription factor family. The study on the detailed binding specificity of the MITF/DNA complex has been a challenge. MITF-DNA interaction details and energetics information at the atomic level are still poorly understood. Focused on two specific MITF/DNA complexes (MITF/E-box and MITF/M-box), molecular dynamics (MD) simulations and binding energy calculations were carried out to investigate the interaction profile of protein/DNA complex. Detailed free energy information and per-residue energy decomposition are provided. The results illuminate that the protein-DNA interactions can enhance the stability of both MITF and two DNAs. Residue N242 in the loop region, besides four residues previously found (R214, R216, R217 and R240), is proposed for the first time as the crucial determinants for MITF and E-box/M-box binding. Our data provide deep insights to understand the interactions of bHLHzip transcription factor proteins with DNA motifs.