Molecular Dynamic Simulations Suggest that P152R Mutation Within MeCP2 Can Lead to Higher DNA Binding Affinity and Loss of Selective Binding to Methylated DNA

摘要

MECP2 gene mutations can cause Rett Syndrome (RTT) - the second largest cause of mental retardation in girls. Studies based on the Methyl-Binding Domain (MBD) of MeCP2 and DNA complex crystals revealed how the mutated residues in the contact surface within DNA affect their binding. On the other hand, other mutations whose residue is not directly involved in the binding, are also related to RTT. In this paper, Molecular Dynamics (MD) and Potential of Mean Force (PMF) were applied to investigate how the MeCP2 P152R mutation influences MBD binding to DNA. The results suggest that the P152R mutation leads to MeCP2 increasing binding affinity towards both methylated and non-methylated DNA and decreasing binding selectivity towards methylated DNA. This may help explain previous inconclusive experimental results relating to the role of the P152R mutation in protein/DNA interactions and subsequent effects in RTT.