Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps)
Autor: | Neha S. Gandhi, Pilar Blancafort, Ricardo L. Mancera |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
iPeps Peptide 010402 general chemistry Engrailed homeodomain 01 natural sciences 03 medical and health sciences Molecular dynamics breast cancer Hox gene Transcription factor transcription factor chemistry.chemical_classification Chemistry 030402 Biomolecular Modelling and Design Rational design Biological activity engrailed molecular dynamics 0104 chemical sciences 030104 developmental biology Oncology 030406 Proteins and Peptides Biophysics Homeobox 060112 Structural Biology (incl. Macromolecular Modelling) iPep Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | The neural-specific transcription factor Engrailed 1 - is overexpressed in basal-like breast tumours. Synthetic interference peptides - comprising a cell-penetrating peptide/nuclear localisation sequence and the Engrailed 1-specific sequence from the N-terminus have been engineered to produce a strong apoptotic response in tumour cells overexpressing EN1, with no toxicity to normal or non Engrailed 1-expressing cells. Here scaled molecular dynamics simulations were used to study the conformational dynamics of these interference peptides in aqueous solution to characterise their structure and dynamics. Transitions from disordered to α-helical conformation, stabilised by hydrogen bonds and proline-aromatic interactions, were observed throughout the simulations. The backbone of the wild-type peptide folds to a similar conformation as that found in ternary complexes of anterior Hox proteins with conserved hexapeptide motifs important for recognition of pre-B-cell leukemia Homeobox 1, indicating that the motif may possess an intrinsic preference for helical structure. The predicted NMR chemical shifts of these peptides are consistent with the Hox hexapeptides in solution and Engrailed 2 NMR data. These findings highlight the importance of aromatic residues in determining the structure of Engrailed 1 interference peptides, shedding light on the rational design strategy of molecules that could be adopted to inhibit other transcription factors overexpressed in other cancer types, potentially including other transcription factor families that require highly conserved and cooperative protein-protein partnerships for biological activity. |
Databáze: | OpenAIRE |
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