The native energy landscape for interleukin-1beta. Modulation of the population ensemble through native-state topology.
The native energy landscape for interleukin-1beta. Modulation of the population ensemble through native-state topology.
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DOI：
10.1016/j.jmb.2005.02.059
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发表时间：
2005-04
影响因子：
5.6
通讯作者：
M. Roy;Leslie L. Chavez;J. Finke;D. Heidary;J. Onuchic;P. Jennings
中科院分区：
文献类型：
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作者：
M. Roy;Leslie L. Chavez;J. Finke;D. Heidary;J. Onuchic;P. Jennings
极简主义 Gō 模型在天然构象中没有能量挫败，已被证明可以准确描述 β-三叶蛋白、白介素-1β (IL-1β) 的折叠途径。虽然这些模型似乎成功地模拟了展开系综和原生系综之间的过渡态和中间体，但尚不清楚它们在能量扰动后如何准确地捕获原生系综内较小但与生物学相关的结构变化。在此，我们解答以下问题。基于天然拓扑结构的白细胞介素 1β 的简单 Gō 模型能否描述随着蛋白质稳定性的改变，天然整体结构特性的变化？或者是否有必要包括更明确的原子、静电、氢键和范德华力的表示来描述这些变化？使用各种实验探针在天然（0M 氯化钠、盐酸胍 (Gdn-HCl)）、中度不稳定（0M 氯化钠、0.8M Gdn-HCl）和中等盐浓度（0.8M 氯化钠、0M Gdn-HCl）下对 IL-1β 的天然整体进行了表征。异核 1H-15N 核欧沃豪塞效应光谱 (NOESY) 和异核单量子相关 (HSQC) NMR 光谱证实，β-三叶形全局折叠在这三种条件下基本完好。然而，当用 0.8M NaCl 或 Gdn-HCl 扰动时，整个链的 153 个残基中的 25 个确实表现出 13 C 和 1 H–15 N 化学位移。尽管稳定 (0M Gdn-HCl) 和不稳定 (0.8M Gdn-HCl) IL-1β 之间所有残基的溶剂氢-氘交换的保护因子存在很大差异，但在稳态 15 N–1H NOE 增强方面没有测量到差异。因此，化学位移与 Gdn-HCl 存在下残留物灵活性的整体但有限的增加相关。极简模拟强调了天然和 0.8M Gdn-HCl 之间位置偏移最大的区域，这是通过实验确定的。这种相关性表明，IL-1β 天然整体内的结构变化至少部分地受最小能量挫败原则的控制。
A minimalist Gō-model, with no energetic frustration in the native conformation, has been shown to describe accurately the folding pathway of the β-trefoil protein, interleukin-1β (IL-1β). While it appears that these models successfully model transition states and intermediates between the unfolded and native ensembles, it is unclear how accurately they capture smaller, yet biologically relevant, structural changes within the native ensemble after energetic perturbation. Here, we address the following questions. Can a simple Gō-model of interleukin-1β, based on native topology, describe changes in structural properties of the native ensemble as the protein stability is changed? Or is it necessary to include a more explicit representation of atoms, electrostatic, hydrogen bonding, and van der Waals forces to describe these changes? The native ensemble of IL-1β was characterized using a variety of experimental probes under native (0M NaCl, guanidine hydrochloride (Gdn-HCl)), moderately destabilized (0M NaCl, 0.8M Gdn-HCl), and in moderate salt concentration (0.8M NaCl, 0M Gdn-HCl). Heteronuclear1H–15N nuclear Overhauser effect spectroscopy (NOESY) and heteronuclear single quantum correlation (HSQC) NMR spectra confirmed that the β-trefoil global fold was largely intact under these three conditions. However, 25 of the 153 residues throughout the chain did demonstrate13C and1H–15N chemical shifts when perturbed with 0.8M NaCl or Gdn-HCl. Despite large differences in protection factors from solvent hydrogen-deuterium exchange for all residues between stable (0M Gdn-HCl) and destabilized (0.8M Gdn-HCl) IL-1β, no difference in steady-state15N–1H NOE enhancements were measured. Thus, the chemical shifts correlate with a global but limited increase in residue flexibility in the presence of Gdn-HCl. Minimalist simulations highlight the regions of greatest position shift between native and 0.8M Gdn-HCl, which were determined experimentally. This correlation demonstrates that structural changes within the native ensemble of IL-1β are, at least partially, governed by the principle of minimal energetic frustration.