P152R Mutation Within MeCP2 Can Cause Loss of DNA-Binding Selectivity

  • Dino FranklinEmail author
Original Research Article


MeCP2 is a protein highly expressed in the brain that participates in the genetic expression and RNA splicing regulation. MeCP2 binds preferably to methylated DNA and other nuclear corepressors to alter chromatin. MECP2 gene mutations can cause rett syndrome (RTT), a severe neurological disorder that affects around one in ten thousand girls. In this paper, Molecular Dynamics (MD) simulations were performed to scrutinize how the MeCP2 P152R mutation influences the protein binding to DNA. Also, the Umbrella Sampling technique was used to obtain the potential mean forces (PMFs) of both wild-type and mutated MeCP2 Methyl-CpG-binding domain (MBD) binding to both non-methylated and methylated DNA. P152R is a common missense mutation in MBD associated with RTT; however, there are no studies that explain how it causes protein dysfunction. The results from this study hypothesize that P152R mutation leads to MBD binding more strongly to DNA, while selectively decreasing binding affinity to methylated DNA. These provide an explanation for previous not conclusive experimental results regarding the mechanism of how this mutation affects the binding of the protein to DNA, and subsequently its effects on RTT. Furthermore, the results of this research-in-progress can be used as the basis for further investigations into the molecular basis of RTT and to potentially reveal a target for therapy in the future.


MeCP2 Rett syndrome DNA-binding Molecular dynamics 





Diagnostic and statistical manual of mental disorders, fourth edition


Free energy perturbation


General amber force field


Gibbs free energy


Histone deacetylases




Methyl-binding domain


Methyl CpG binding protein 2


Methyl CpG binding protein 2 gene




Molecular dynamics


Potential of mean force


Protein data bank


Restrained electrostatic potential


Root mean square deviation


Root mean square fluctuations




Solvent accessibility surface


Transcriptional repression domain


Weight histogram analysis method



This work was supported by FAPEMIG (Grant Number: APQ-01821-11).

Compliance with Ethical Standards

Conflict of interest

The author declares no conflicts of interest in relation to this work.

Supplementary material

12539_2019_316_MOESM1_ESM.tiff (13.6 mb)
Figure S1. Wildtype of the MeCP2 MBD C-α Covariance Matrices. Obtained from 100ns of non-restrained MD simulations. (TIFF 13913 KB)
12539_2019_316_MOESM2_ESM.tiff (13.6 mb)
Figure S2. P152R mutant of the MeCP2 MBD C-α Covariance Matrices. Obtained from 100ns of non-restrained MD simulations. (TIFF 13913 KB)
12539_2019_316_MOESM3_ESM.tiff (438 kb)
Figure S3. MeCP2 MBDs C-α Root Mean Square Fluctuations (RMSF). The RMSF for the wild-type MBD is plotted in black and plotted in red for the mutated MBD. (TIFF 438 KB)


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Copyright information

© International Association of Scientists in the Interdisciplinary Areas 2019

Authors and Affiliations

  1. 1.Faculty of ComputingFederal University of UberlandiaUberlândiaBrazil

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