@article {101166,
	title = {All-Atom Model for Stabilization of α-Helical Structure in Peptides by Hydrocarbon Staples},
	journal = {J. Am. Chem. Soc.},
	volume = {131},
	year = {2009},
	month = {2009},
	pages = {4622 - 4627},
	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.},
	url = {http://dx.doi.org/10.1021/ja805037p},
	author = {Peter S. Kutchukian and Yang, Jae Shick and Verdine, Gregory L. and Eugene I. Shakhnovich}
}
