title: Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.
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.
authors.affiliation: Bioinformatics Institute, ASTAR (Agency for Science, Technology and Research), Biopolis, Singapore, Singapore.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Joseph
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D012996:Solutions
chemical_list: C474007:Bax protein (53-86); D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012996:Solutions