Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps)
© Gandhi et al. The neural-specific transcription factor Engrailed 1 - is overexpressed in basallike 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...
| Main Authors: | , , |
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| Format: | Journal Article |
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Impact Journals LLC
2018
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| Online Access: | http://hdl.handle.net/20.500.11937/67526 |
| _version_ | 1848761589051686912 |
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| author | Gandhi, Neha Blancafort, P. Mancera, Ricardo |
| author_facet | Gandhi, Neha Blancafort, P. Mancera, Ricardo |
| author_sort | Gandhi, Neha |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | © Gandhi et al. The neural-specific transcription factor Engrailed 1 - is overexpressed in basallike 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 a-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. |
| first_indexed | 2025-11-14T10:34:04Z |
| format | Journal Article |
| id | curtin-20.500.11937-67526 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:34:04Z |
| publishDate | 2018 |
| publisher | Impact Journals LLC |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-675262018-05-18T08:05:22Z Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps) Gandhi, Neha Blancafort, P. Mancera, Ricardo © Gandhi et al. The neural-specific transcription factor Engrailed 1 - is overexpressed in basallike 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 a-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. 2018 Journal Article http://hdl.handle.net/20.500.11937/67526 10.18632/oncotarget.25025 Impact Journals LLC restricted |
| spellingShingle | Gandhi, Neha Blancafort, P. Mancera, Ricardo Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps) |
| title | Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps) |
| title_full | Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps) |
| title_fullStr | Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps) |
| title_full_unstemmed | Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps) |
| title_short | Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps) |
| title_sort | atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (en1-ipeps) |
| url | http://hdl.handle.net/20.500.11937/67526 |