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

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Abstract

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.

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Abbreviations

5mC:

5-methylcytosine

DSM-IV:

Diagnostic and statistical manual of mental disorders, fourth edition

FEP:

Free energy perturbation

GAFF:

General amber force field

∆G:

Gibbs free energy

HDAC:

Histone deacetylases

NPT:

Isothermal–isobaric

MBD:

Methyl-binding domain

MeCP2:

Methyl CpG binding protein 2

MECP2:

Methyl CpG binding protein 2 gene

MetDNA:

Methylated-DNA

MD:

Molecular dynamics

PMF:

Potential of mean force

PDB:

Protein data bank

RESP:

Restrained electrostatic potential

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuations

SeMet:

Selenomethionine

SAS:

Solvent accessibility surface

TRD:

Transcriptional repression domain

WHAM:

Weight histogram analysis method

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Funding

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

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Authors and Affiliations

  1. Faculty of Computing, Federal University of Uberlandia, Uberlândia, Brazil

    Dino Franklin

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  1. Dino Franklin
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Correspondence to Dino Franklin.

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

Electronic supplementary material

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Figure S1

. Wildtype of the MeCP2 MBD C-α Covariance Matrices. Obtained from 100ns of non-restrained MD simulations. (TIFF 13913 KB)

Figure S2

. P152R mutant of the MeCP2 MBD C-α Covariance Matrices. Obtained from 100ns of non-restrained MD simulations. (TIFF 13913 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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Franklin, D. P152R Mutation Within MeCP2 Can Cause Loss of DNA-Binding Selectivity. Interdiscip Sci Comput Life Sci 11, 10–20 (2019). https://doi.org/10.1007/s12539-019-00316-z

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