Conformational flexibility and rotational binding shifts in W104C mutant MECP2-DNA complexes: A molecular simulation study.

Methyl-CpG-binding proteins are crucial epigenetic regulators associated with inborn genetic and neurodevelopmental disorders such as Rett Syndrome, Autism Spectrum Disorder, and Angelman Syndrome, as well as various malignancies, including colorectal, prostate, brain, breast, and endometrial cancers. The proteins that belong to Methyl Binding Domain (MBD) superfamily, have eleven members: SETDB1, SETDB2, MECP2, MBD1-6, BAZ2A, and BAZ2B. This research utilized both sequence-based and structure-based methodologies to ascertain the most detrimental mutation in MBD proteins. The W104C mutation in MECP2 was recognized as the most damaging alteration. Structure prediction and stereochemical evaluation were succeeded by 500 ns all-atom molecular dynamics simulation to evaluate conformational alterations. The docking of wild type and W104C mutant MECP2 onto the targeted gene BDNF, demonstrated variations in docking geometry. Parameters including RMSD and Rg, indicated structural divergence and decreased DNA-binding efficacy in the mutant, coupled with solvent exposure. W104C disrupts stable DNA binding by MECP2 via inducing conformational instability and impairing hydrogen bond donor-acceptor activity, leading to fluctuating rotation angles and inconsistent binding energies throughout the simulation. Analysis of the interaction profile indicated the loss of critical residues (Y121, R133) and acquisition of new residues (R115, A117 and R168) in the mutant, hence modifying electrostatic equilibrium. Electrostatic surface mapping revealed an almost consistent surface potential within wild type binding cavity but the mutant demonstrated a fluctuating surface charge distribution, indicating less affinity. The severity of deregulation of wild type MECP2 activity by W104C, prompting inborn genetic diseases, Rett syndrome, could further be experimentally tested.