Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations
Atomistic simulations of a set of stapled alpha helical peptides derived from the BH3 helix of MCL-1 (Stewart et al. (2010) Nat Chem Biol 6: 595–601) complexed to a fragment (residues 172–320) of MCL-1 revealed that the highest affinity is achieved when the staples engage the surface of MCL-1 as has...
| Main Authors: | , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2013
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| Online Access: | https://hdl.handle.net/10356/95173 http://hdl.handle.net/10220/9289 |
| _version_ | 1824454542679343104 |
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| author | Joseph, Thomas L. Lane, David P. Verma, Chandra Shekhar. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Joseph, Thomas L. Lane, David P. Verma, Chandra Shekhar. |
| author_sort | Joseph, Thomas L. |
| collection | NTU |
| description | Atomistic simulations of a set of stapled alpha helical peptides derived from the BH3 helix of MCL-1 (Stewart et al. (2010) Nat Chem Biol 6: 595–601) complexed to a fragment (residues 172–320) of MCL-1 revealed that the highest affinity is achieved when the staples engage the surface of MCL-1 as has also been demonstrated for p53-MDM2 (Joseph et al. (2010) Cell Cycle 9: 4560–4568; Baek et al. (2012) J Am Chem Soc 134: 103–106). Affinity is also modulated by the ability of the staples to pre-organize the peptides as helices. Molecular dynamics simulations of these stapled BH3 peptides were carried out followed by determination of the energies of interactions using MM/GBSA methods. These show that the location of the staple is a key determinant of a good binding stapled peptide from a bad binder. The good binder derives binding affinity from interactions between the hydrophobic staple and a hydrophobic patch on MCL-1. The position of the staple was varied, guiding the design of new stapled peptides with higher affinities. |
| first_indexed | 2025-02-19T03:23:58Z |
| format | Journal Article |
| id | ntu-10356/95173 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:23:58Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | ntu-10356/951732023-02-28T17:03:57Z Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations Joseph, Thomas L. Lane, David P. Verma, Chandra Shekhar. School of Biological Sciences Atomistic simulations of a set of stapled alpha helical peptides derived from the BH3 helix of MCL-1 (Stewart et al. (2010) Nat Chem Biol 6: 595–601) complexed to a fragment (residues 172–320) of MCL-1 revealed that the highest affinity is achieved when the staples engage the surface of MCL-1 as has also been demonstrated for p53-MDM2 (Joseph et al. (2010) Cell Cycle 9: 4560–4568; Baek et al. (2012) J Am Chem Soc 134: 103–106). Affinity is also modulated by the ability of the staples to pre-organize the peptides as helices. Molecular dynamics simulations of these stapled BH3 peptides were carried out followed by determination of the energies of interactions using MM/GBSA methods. These show that the location of the staple is a key determinant of a good binding stapled peptide from a bad binder. The good binder derives binding affinity from interactions between the hydrophobic staple and a hydrophobic patch on MCL-1. The position of the staple was varied, guiding the design of new stapled peptides with higher affinities. Published version 2013-02-27T06:48:19Z 2019-12-06T19:09:36Z 2013-02-27T06:48:19Z 2019-12-06T19:09:36Z 2012 2012 Journal Article Joseph, T. L., Lane, D. P., & Verma, C. S. (2012). Stapled BH3 Peptides against MCL-1: Mechanism and Design Using Atomistic Simulations. PLoS ONE, 7(8). 1932-6203 https://hdl.handle.net/10356/95173 http://hdl.handle.net/10220/9289 10.1371/journal.pone.0043985 22952838 en PLoS ONE © 2012 The Authors. application/pdf |
| spellingShingle | Joseph, Thomas L. Lane, David P. Verma, Chandra Shekhar. Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations |
| title | Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations |
| title_full | Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations |
| title_fullStr | Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations |
| title_full_unstemmed | Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations |
| title_short | Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations |
| title_sort | stapled bh3 peptides against mcl 1 mechanism and design using atomistic simulations |
| url | https://hdl.handle.net/10356/95173 http://hdl.handle.net/10220/9289 |
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