Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.

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...

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Autores principales:	Thomas L Joseph, David P Lane, Chandra S Verma
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fffe6b2a38e8478b87a25c55fafbf269
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spelling	oai:doaj.org-article:fffe6b2a38e8478b87a25c55fafbf2692021-11-18T07:06:54ZStapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.1932-620310.1371/journal.pone.0043985https://doaj.org/article/fffe6b2a38e8478b87a25c55fafbf2692012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22952838/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Atomistic 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.Thomas L JosephDavid P LaneChandra S VermaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e43985 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thomas L Joseph David P Lane Chandra S Verma Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.
description	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.
format	article
author	Thomas L Joseph David P Lane Chandra S Verma
author_facet	Thomas L Joseph David P Lane Chandra S Verma
author_sort	Thomas L Joseph
title	Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.
title_short	Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.
title_full	Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.
title_fullStr	Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.
title_full_unstemmed	Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.
title_sort	stapled bh3 peptides against mcl-1: mechanism and design using atomistic simulations.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/fffe6b2a38e8478b87a25c55fafbf269
work_keys_str_mv	AT thomasljoseph stapledbh3peptidesagainstmcl1mechanismanddesignusingatomisticsimulations AT davidplane stapledbh3peptidesagainstmcl1mechanismanddesignusingatomisticsimulations AT chandrasverma stapledbh3peptidesagainstmcl1mechanismanddesignusingatomisticsimulations
_version_	1718423956006895616

Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations.

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