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.
Highlights
Apoptosis is a conserved process that leads to cell death
We have carried out molecular dynamics (MD) studies investigating the binding of 6 BH3 peptides to MCL-1; these peptides have been experimentally characterized by Walensky and colleagues [24]
Our simulations of the interactions of these peptides with MCL-1 guided the design of an additional six stapled BH3 peptides (which we shall refer to as BH3F-BH3K; we will further refer to the wild type peptide as BH3wt and their 5 stapled peptides as BH3ABH3E (Table 1))
Summary
Apoptosis is a conserved process that leads to cell death. There are two recognized pathways that lead to apoptosis: ‘‘extrinsic’’ and ‘‘intrinsic’’ [2]. The most characterized intrinsic pathway is mitochondrial and is controlled by the B-cell lymphoma 2 (Bcl-2) protein family [4]. The Bcl-2 protein family comprises suppressors (e.g., Bcl-2, Bcell lymphoma-extra large, or Bcl-XL myeloid cell leukemia sequence 1 or MCL-1) or promoters (e.g., Bcl associated X protein or Bax, Bcl-2 homologous antagonist/killer or Bak, BH3only proteins including Bim, Bid) of apoptosis [5]. Various apoptotic stimuli trigger the release of factors (eg Cytochrome c) from the mitochondria that activate caspases. Bcl-2 related proteins appear to modulate the release of Cytochrome c [6]
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