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A Compact Native 24-Residue Supersecondary Structure Derived from the Villin Headpiece Subdomain

机译:从Villin头饰子域派生的紧凑型本机24残留超二级结构

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摘要

Many small proteins fold highly cooperatively in an all-or-none fashion and thus their native states are well protected from thermal fluctuations by an extensive network of interactions across the folded structure. Because protein structures are stabilized by local and nonlocal interactions among distal residues, dissecting individual substructures from the context of folded proteins results in large destabilization and loss of unique three-dimensional structure. Thus, mini-protein substructures can only rarely be derived from natural templates. Here, we describe a compact native 24-residues-long supersecondary structure derived from the hyperstable villin headpiece subdomain consisting of helices 2 and 3 (HP24). Using a combination of experimental techniques, including NMR and small-angle x-ray scattering, as well as all-atom replica exchange molecular-dynamics simulations, we show that a variant with stabilizing substitutions (HP24stab) forms a densely packed and compact conformation. In HP24stab, interactions between helices 2 and 3 are similar to those observed in native folded HP35, and the two helices cooperatively stabilize each other by completing the hydrophobic core lining the central part of HP35. Interestingly, even though the HP24wt fragment shows a more expanded and less structured conformation, NMR and simulations demonstrate a preference for a native-like topology. Thus, the two stabilizing residues in HP24stab shift the energy balance toward the native state, leading to a minimal folding motif.
机译:许多小蛋白质以全有或全无的方式高度协作地折叠,因此,通过折叠结构上广泛的相互作用网络,可以很好地保护其天然状态免受热波动的影响。因为蛋白质结构通过远端残基之间的局部和非局部相互作用而得以稳定,所以将单个亚结构与折叠的蛋白质相分离会导致较大的不稳定并失去独特的三维结构。因此,小蛋白亚结构只能很少来自天然模板。在这里,我们描述了一个紧凑的原生24残基长的超二级结构,该结构来自由2和3螺旋(HP24)组成的超稳定villin头戴式子域。通过结合使用NMR和小角度X射线散射等实验技术以及全原子复制子交换分子动力学模拟,我们显示了具有稳定取代基的变体(HP24stab)形成了密集且紧凑的构象。在HP24stab中,螺旋2和3之间的相互作用类似于在天然折叠的HP35中观察到的相互作用,并且两个螺旋通过完成衬在HP35中心部分的疏水核而彼此协同稳定。有趣的是,即使HP24wt片段显示出更大的扩展性和更少的结构构象,NMR和模拟也显示出对类似天然拓扑的偏好。因此,HP24stab中的两个稳定残基使能量平衡朝着天然状态转移,从而导致最小的折叠基序。

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