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|Title:||Stapled BH3 Peptides against MCL-1: Mechanism and Design Using Atomistic Simulations||Authors:||Joseph, T.L.
|Issue Date:||31-Aug-2012||Citation:||Joseph, T.L., Lane, D.P., Verma, C.S. (2012-08-31). Stapled BH3 Peptides against MCL-1: Mechanism and Design Using Atomistic Simulations. PLoS ONE 7 (8) : -. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0043985||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. © 2012 Joseph et al.||Source Title:||PLoS ONE||URI:||http://scholarbank.nus.edu.sg/handle/10635/101719||ISSN:||19326203||DOI:||10.1371/journal.pone.0043985|
|Appears in Collections:||Staff Publications|
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