All-Atom Model for Stabilization of α-Helical Structure in Peptides by Hydrocarbon Staples

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All-Atom Model for Stabilization of α-Helical Structure in Peptides by Hydrocarbon Staples

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Title: All-Atom Model for Stabilization of α-Helical Structure in Peptides by Hydrocarbon Staples
Author: Kutchukian, Peter S.; Yang, Jae Shick; Verdine, Gregory L.; Shakhnovich, Eugene Isaacovitch

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Citation: Kutchukian, Peter S., Jae Shick Yang, Gregory L. Verdine, and Eugene I. Shakhnovich. 2009. “All-Atom Model for Stabilization of α-Helical Structure in Peptides by Hydrocarbon Staples.” Journal of the American Chemical Society 131 (13) (April 8): 4622–4627. doi:10.1021/ja805037p. http://dx.doi.org/10.1021/ja805037p.
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Abstract: Recent work has shown that the incorporation of an all-hydrocarbon “staple” into peptides can greatly increase their α-helix propensity, leading to an improvement in pharmaceutical properties such as proteolytic stability, receptor affinity and cell-permeability. Stapled peptides thus show promise as a new class of drugs capable of accessing intractable targets such as those that engage in intracellular protein-protein interactions. The extent of α-helix stabilization provided by stapling has proven to be substantially context dependent, requiring cumbersome screening to identify the optimal site for staple incorporation. In certain cases, a staple encompassing one turn of the helix (attached at residues i and i+4) furnishes greater helix stabilization than one encompassing two turns (i,i+7 staple), which runs counter to expectation based on polymer theory. These findings highlight the need for a more thorough understanding of the forces that underlie helix stabilization by hydrocarbon staples. Here we report all-atom Monte Carlo folding simulations comparing unmodified peptides derived from RNAse A and BID BH3 with various i,i+4 and i,i+7 stapled versions thereof. The results of these simulations were found to be in quantitative agreement with experimentally determined helix propensities. We also discovered that staples can stabilize quasi-stable decoy conformations, and that the removal of these states plays a major role in determining the helix stability of stapled peptides. Finally, we critically investigate why our method works, exposing the underlying physical forces that stabilize stapled peptides.
Published Version: doi:10.1021/ja805037p
Other Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735086/
Terms of Use: This article is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#OAP
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33464143
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