Research Papers:

Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps)

Neha S. Gandhi _, Pilar Blancafort and Ricardo L. Mancera

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Oncotarget. 2018; 9:22383-22397. https://doi.org/10.18632/oncotarget.25025

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Neha S. Gandhi1, Pilar Blancafort2 and Ricardo L. Mancera3

1School of Mathematical Sciences and Institute for Health and Biomedical Innovation, Queensland University of Technology, Gardens Point Campus, Brisbane QLD 4000, Australia

2Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, Perth WA 6009, Australia

3School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute and Curtin Institute for Computation, Curtin University, Perth WA 6845, Australia

Correspondence to:

Neha S. Gandhi, email: [email protected]

Ricardo L. Mancera, email: [email protected]

Keywords: Engrailed homeodomain; transcription factor; iPep; breast cancer; molecular dynamics

Received: July 27, 2017     Accepted: March 15, 2018     Published: April 27, 2018


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.

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