The role of the unfolded state in hairpin stability
The role of the unfolded state in hairpin stability
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DOI：
10.1016/s0006-3495(03)74771-7
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发表时间：
2003-12-01
影响因子：
3.4
通讯作者：
Smith, PE
中科院分区：
文献类型：
--
作者：
Lei, HX;Smith, PE
研究了 T3S 突变对 3:5 β-发夹形成肽 (YITNSNGTWT) 稳定性的影响。在纯水中的分子动力学模拟表明，野生型肽形成稳定的发夹，而 T3S 突变体则没有，这与实验数据一致。 Thr到Ser突变的热力学积分计算表明，折叠状态下的自由能变化很小，但未折叠状态下的相应变化很大且有利。造成这种差异的主要原因之一似乎是涉及 Tyr1 和 Ser3 羟基的稳定簇的形成及其与 C 末端羧酸基团的相互作用，这是在 T3S 突变体解折叠后观察到的。对Thr和Ser侧链偏好的进一步分析表明，由于Thr chi(1)二面体对g(+)态的高度偏好，野生型肽中相应的簇不稳定，这似乎与稳定簇的形成不相容。结果表明，在试图充分解释突变对发夹稳定性的影响时，应该考虑未折叠状态的性质。
The effects of a T3S mutation on the stability of a 3:5 beta-hairpin forming peptide (YITNSNGTWT) are investigated. Molecular dynamics simulations in explicit water indicate that the wild-type peptide forms a stable hairpin whereas the T3S mutant does not, in agreement with the experimental data. Thermodynamic integration calculations for the mutation of Thr to Ser suggest that the free-energy changes in the folded state are small, but the corresponding changes in the unfolded state are large and favorable. One of the main reasons for the difference appears to be the formation of a stable cluster involving the Tyr1 and Ser3 hydroxyl groups and their interaction with the C-terminal carboxylate group, which was observed after unfolding of the T3S mutant. Further analysis of the side-chain preferences of Thr and Ser indicate that the corresponding cluster in the wildtype peptide is unstable due to the high preference of the Thr chi(1) dihedral for g(+) states, which appeared to be incompatible with formation of a stable cluster. The results suggest that one should consider the nature of the unfolded state when attempting to fully explain the effects of mutations on hairpin stability.