Breed J, Kerr I D, Molle G, Duclohier H, Sansom M S
Laboratory of Molecular Biophysics, University of Oxford, UK.
Biochim Biophys Acta. 1997 Dec 4;1330(2):103-9. doi: 10.1016/s0005-2736(97)00163-6.
Several analogues of the channel-forming peptaibol alamethicin have been demonstrated to exhibit faster switching between channel substates than does unmodified alamethicin. Molecular modelling studies are used to explore the possible molecular basis of these differences. Models of channels formed by alamethicin analogues were generated by restrained molecular dynamics in vacuo and refined by short molecular dynamics simulations with water molecules within and at either mouth of the channel. A decrease in backbone solvation was found to correlate with a decrease in open channel stability between alamethicin and an analogue in which all alpha-amino-isobutyric acid residues of alamethicin were replaced by leucine. A decrease in the extent of hydrogen-bonding at residue 7 correlates with lower open channel stabilities of analogues in which the glutamine at position 7 was replaced by smaller polar sidechains. These two observations indicate the importance of alamethicin/water H-bonds in stabilizing the open channel.
已证明几种形成通道的肽抗生素阿拉米辛类似物在通道亚状态之间切换的速度比未修饰的阿拉米辛更快。分子建模研究用于探索这些差异可能的分子基础。通过在真空中进行受限分子动力学生成阿拉米辛类似物形成的通道模型，并通过在通道内部和通道口处有水分子存在的短分子动力学模拟进行优化。发现主链溶剂化程度的降低与阿拉米辛和一种将阿拉米辛所有α-氨基异丁酸残基替换为亮氨酸的类似物之间开放通道稳定性的降低相关。残基7处氢键程度的降低与将位置7的谷氨酰胺替换为较小极性侧链的类似物较低的开放通道稳定性相关。这两个观察结果表明阿拉米辛/水氢键在稳定开放通道中的重要性。
