Haney Conor M, Werner Halina M, McKay James J, Horne W Seth
Department of Chemistry, University of Pittsburgh, 219 Parkman Ave., Pittsburgh, PA 15260, USA.
Org Biomol Chem. 2016 Jun 15;14(24):5768-73. doi: 10.1039/c6ob00475j.
Peptide cross-linking has been widely explored as a means of constraining short sequences into stable folded conformations, most commonly α-helices. The prevailing hypothesis for the origin of helix stabilization is an entropic effect resulting from backbone pre-organization; however, obtaining direct evidence bearing on this hypothesis is challenging. Here, we compare the folding thermodynamics of a small helix-rich protein domain and analogues containing one of three common cross-linking motifs. Analysis of the folding free energy landscapes of linear vs. cyclized species reveal consistent trends in the effect of cyclization on folding energetics, as well as subtle differences based on the chemistry of the cross link. Stabilization in all three systems arises entirely from a reduction in the entropic penalty of folding that more than compensates for an enthalpic destabilization of the folded state.
肽交联作为一种将短序列约束成稳定折叠构象（最常见的是α-螺旋）的方法已被广泛研究。关于螺旋稳定起源的主流假说是由主链预组织产生的熵效应；然而，获得支持这一假说的直接证据具有挑战性。在这里，我们比较了一个富含螺旋的小蛋白质结构域和含有三种常见交联基序之一的类似物的折叠热力学。对线性与环化物种的折叠自由能景观分析揭示了环化对折叠能量学影响的一致趋势，以及基于交联化学的细微差异。所有三个系统中的稳定化完全源于折叠熵罚的降低，这足以补偿折叠态的焓不稳定。
