title: Effects of mutants in bHLH region on structure stability and protein-DNA binding energy in DECs.
abstract: The human DEC subfamily contains two highly conserved members belonging to basic helix-loop-helix (bHLH) transcription factors. This conserved family is spread widely among various species with the function of regulating various crucial molecular signaling pathways. Due to the significance of DECs for important biological processes, their relationship with diseases and the lack of experimentally proven structures, we have implemented a comparative modeling for the bHLH region of DECs as homodimers with themselves and heterodimers with HES-1. Three mutants with predicted roles in reducing intramolecular binding (H57A, R65A, and LL7879AA in DEC1 and LL7071AA in DEC2) were investigated on DEC monomers. Molecular dynamics (MD) simulations were also employed to evaluate the behavior of the mutant molecules in aqueous solution. The monomer was divided into subregions for accurate investigation. The fluctuation in the basic region of mutants was higher than that of wild-type molecules. The binding energy value between protein and DNA obviously increased in the homodimer harboring R65A mutants, which led to more unstable status between protein and DNA. Thus, the mutant R65A interfered DNA-binding affinity. A study on the spatial structures of wild-type and mutant DECs may facilitate functional prediction for mutation effects and dynamic behavior under various conditions and may ultimately help in targeted drug design.
authors: a Central Laboratory , Jinan Central Hospital Affiliated to Shandong University , No. 105 Jiefang Road, Jinan 250013 , Shandong Province , P.R. China.
authors: Yi
authors: Y
authors: Kong
authors: b Department of Oncology , Zhang Qiu People Hospital , No. 1920 Huiquan Road, Zhangqiu 250200 , Shandong Province , P.R. China.
authors: Zhen
authors: Z
authors: Wang
authors: a Central Laboratory , Jinan Central Hospital Affiliated to Shandong University , No. 105 Jiefang Road, Jinan 250013 , Shandong Province , P.R. China.
authors: Yanfei
authors: Y
authors: Jia
authors: a Central Laboratory , Jinan Central Hospital Affiliated to Shandong University , No. 105 Jiefang Road, Jinan 250013 , Shandong Province , P.R. China.
authors: Ping
authors: P
authors: Li
authors: a Central Laboratory , Jinan Central Hospital Affiliated to Shandong University , No. 105 Jiefang Road, Jinan 250013 , Shandong Province , P.R. China.
authors: Shuhua
authors: S
authors: Hao
authors: a Central Laboratory , Jinan Central Hospital Affiliated to Shandong University , No. 105 Jiefang Road, Jinan 250013 , Shandong Province , P.R. China.
authors: Yunshan
authors: Y
authors: Wang
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry* / Q000235:genetics; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D019281:Dimerization; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004268:DNA-Binding Proteins
keywords: DEC1/2; DNA-binding affinity; molecular dynamics simulation; protein comparative modeling