Computational modeling of the bHLH domain of the transcription factor TWIST1 and R118C, S144R and K145E mutants

BMC Bioinformatics

Research Article

Ernesto R Caffarena¹  João HM da Silva¹  Amanda M Maia²  André L Mencalha²  Eliana Abdelhay² 

[1] Laboratório de Biofísica Computacional e Modelagem Molecular – PROCC/ FIOCRUZ, Av Brasil, 4365, Manguinhos, Rio de Janeiro/RJ, Brasil;Laboratório de Célula-tronco – CEMO/INCA, Praça da Cruz Vermelha 23 6 andar, Centro, Rio de Janeiro/RJ, Brasil;

关键词: Twist1;    Transcription factor;    bHLH;    Comparative modeling;    Molecular dynamics simulation;    Collective motions;   

DOI  :  10.1186/1471-2105-13-184

 received in 2012-02-16, accepted in 2012-07-17,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundHuman TWIST1 is a highly conserved member of the regulatory basic helix-loop-helix (bHLH) transcription factors. TWIST1 forms homo- or heterodimers with E-box proteins, such as E2A (isoforms E12 and E47), MYOD and HAND2. Haploinsufficiency germ-line mutations of the twist1 gene in humans are the main cause of Saethre-Chotzen syndrome (SCS), which is characterized by limb abnormalities and premature fusion of cranial sutures. Because of the importance of TWIST1 in the regulation of embryonic development and its relationship with SCS, along with the lack of an experimentally solved 3D structure, we performed comparative modeling for the TWIST1 bHLH region arranged into wild-type homodimers and heterodimers with E47. In addition, three mutations that promote DNA binding failure (R118C, S144R and K145E) were studied on the TWIST1 monomer. We also explored the behavior of the mutant forms in aqueous solution using molecular dynamics (MD) simulations, focusing on the structural changes of the wild-type versus mutant dimers.ResultsThe solvent-accessible surface area of the homodimers was smaller on wild-type dimers, which indicates that the cleft between the monomers remained more open on the mutant homodimers. RMSD and RMSF analyses indicated that mutated dimers presented values that were higher than those for the wild-type dimers. For a more careful investigation, the monomer was subdivided into four regions: basic, helix I, loop and helix II. The basic domain presented a higher flexibility in all of the parameters that were analyzed, and the mutant dimer basic domains presented values that were higher than the wild-type dimers. The essential dynamic analysis also indicated a higher collective motion for the basic domain.ConclusionsOur results suggest the mutations studied turned the dimers into more unstable structures with a wider cleft, which may be a reason for the loss of DNA binding capacity observed for in vitro circumstances.

【 授权许可】

Unknown   
© Maia et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.