Targeting MLL-CXXC Domain with Synthetic CpG Dinucleotides: Docking and Molecular Dynamics Simulation Based Approach

Abstract

Mixed lineage leukemia (MLL) is an aggressive type of childhood leukemia characterized by the presence of MLL fusion proteins resultant of chromosomal translocations affecting the MLL gene. These resulting chimeric proteins act as transcriptional regulators that take control of MLL targets. MLL fuses with more than 60 different partner genes, these fusion proteins retain the CXXC domain which binds to nonmethylated CpG DNA. The Molecular docking of CXXC domain and CpG dinucleotides were performed, large scale and long time (10 ns each) molecular dynamics simulation on CXXC domain wild type and AF9-MLL Fusion Protein have been performed to study the mechanism at atomic level. The effects of point mutation on DNA bindings were also studied through Molecular Docking. The results confirm that this point mutation have efficacy of interrupt the DNA bindings. Moreover, in-silico studies suggest external synthetic CpG DNA efficiently binds to CXXC domain and may be potential lead molecule for further in-vitro studies.