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|Title:||Stapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulations||Authors:||Joseph, Thomas L.
Lane, David P.
Verma, Chandra Shekhar.
|Issue Date:||2012||Source:||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).||Series/Report no.:||PLoS ONE||Abstract:||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.||URI:||https://hdl.handle.net/10356/95173
|ISSN:||1932-6203||DOI:||10.1371/journal.pone.0043985||Rights:||© 2012 The Authors.||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Journal Articles|
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