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dc.contributor.authorJoseph, Thomas L.en
dc.contributor.authorLane, David P.en
dc.contributor.authorVerma, Chandra Shekhar.en
dc.identifier.citationJoseph, 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).en
dc.description.abstractAtomistic 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.en
dc.relation.ispartofseriesPLoS ONEen
dc.rights© 2012 The Authors.en
dc.titleStapled BH3 Peptides against MCL-1 : mechanism and design using atomistic simulationsen
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen
dc.description.versionPublished versionen
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