Exploring the impact of polyproline II (PII) conformational bias on the binding of peptides to the SEM-5 SH3 domain.
Exploring the impact of polyproline II (PII) conformational bias on the binding of peptides to the SEM-5 SH3 domain.
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探索聚脯氨酸 II (PII) 构象偏差对肽与 SEM-5 SH3 结构域结合的影响。
DOI：
10.1110/ps.033647.107
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Hilser,VincentJ
中科院分区：
文献类型：
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作者：
Whitten,StevenT;Yang,Huan-Wang;Fox,RobertO;Hilser,VincentJ
据观察，左手聚脯氨酸 II 螺旋结构 (PII) 是蛋白质和小多肽链无序状态下的主要构象，即使序列中不存在脯氨酸。最近，在 Ferreon 和 Hilser 的工作中，通过测量 Sos 肽变体与 SEM-5 的 C 端 Src 同源 3 结构域的结合能量，通过量热法确定了与表面暴露的脯氨酸位点处的 Ala 和 Gly 取代相关的能量。结果被解释为对结合构象（即 PII）的显着构象偏差，即使配体未结合。然而，该研究无法确定肽的构象偏差是否可以用 PII 偏好以外的术语来解释。在这里，我们使用基于硬球碰撞 (HSC) 模型的计算机算法来测试肽配体未结合状态的偏差是否特定于 PII 构象的概念，或者对 (φ, ψ) 空间的任何其他区域的偏差是否也可以导致相同的观察到的结合能量。这些计算机模拟的结果表明，在为小肽偏差建模的 (φ, ψ) 区域中，只有 PII 构象的偏差，并且以与实验观察到的偏差率相似的偏差率定量地再现了实验结合能量。
The left‐handed polyproline II helical structure (PII) is observed to be a dominant conformation in the disordered states of protein and small polypeptide chains, even when no prolines are present in the sequence. Recently, in work by Ferreon and Hilser, the energetics associated with Ala and Gly substitutions at a surface exposed proline site were determined calorimetrically by measuring the binding energetics of Sos peptide variants to the C‐terminal Src Homology 3 domain of SEM‐5. The results were interpreted as a significant conformational bias toward the bound conformation (i.e., PII), even when the ligand is unbound. That study was not able to determine, however, whether the conformational bias of the peptides could be explained in terms other than that of a PIIpreference. Here, we test, using a computer algorithm based on the hard sphere collision (HSC) model, the notion of whether a bias in the unbound states of the peptide ligands is specific for the PIIconformation, or if a bias to any other region of (φ, ψ) space can also result in the same observed binding energetics. The results of these computer simulations indicate that, of the regions of (φ, ψ) modeled for bias in the small peptides, only the bias to the PIIconformation, and at rates of bias similar to the experimentally observed rates, quantitatively reproduced the experimental binding energetics.