All-Atom Model for Stabilization of α-Helical Structure in Peptides by Hydrocarbon Staples
All-Atom Model for Stabilization of α-Helical Structure in Peptides by Hydrocarbon Staples
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DOI：
10.1021/ja805037p
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发表时间：
2009-04-08
影响因子：
15
通讯作者：
Shakhnovich, Eugene I.
中科院分区：
文献类型：
--
作者：
Kutchukian, Peter S.;Yang, Jae Shick;Shakhnovich, Eugene I.
最近的研究表明，将全烃“钉合物”掺入肽中可以大大增加其α-螺旋倾向，从而改善药物性质，如蛋白水解稳定性、受体亲和力和细胞渗透性。因此，钉合肽显示出作为一类新的药物的前景，能够访问棘手的目标，如那些从事细胞内蛋白质-蛋白质相互作用。已证明吻合提供的α-螺旋稳定程度基本上取决于环境，需要进行繁琐的筛选以确定吻合钉掺入的最佳位点。在某些情况下，包含一个螺旋转角的钉合（在残基i和i+4处连接）比包含两个转角的钉合（i，i+7钉合）具有更大的螺旋稳定性，这与基于聚合物理论的预期相反。这些发现强调了需要更彻底的理解的力量，根据螺旋稳定的碳氢化合物斯台普斯。在这里，我们报告了全原子Monte Carlo折叠模拟，将来自RNA酶A和BID BH 3的未修饰肽与其各种i，i+4和i，i+7钉合版本进行比较。这些模拟的结果被发现是在定量协议与实验确定的螺旋倾向。我们还发现，斯台普斯可以稳定准稳定的诱饵构象，并且这些状态的去除在确定订书肽的螺旋稳定性中起着重要作用。最后，我们批判性地研究了为什么我们的方法有效，揭示了稳定钉合肽的潜在物理力量。
Recent work has shown that the incorporation of an all-hydrocarbon "staple" into peptides can greatly increase their alpha-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 alpha-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.