pH-dependent stability of a decalysine α-helix studied by explicit-solvent molecular dynamics simulations at constant pH
pH-dependent stability of a decalysine α-helix studied by explicit-solvent molecular dynamics simulations at constant pH
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DOI：
10.1021/jp037841n
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发表时间：
2004-09-02
影响因子：
3.3
通讯作者：
Hünenberger, PH
中科院分区：
文献类型：
--
作者：
Börjesson, U;Hünenberger, PH
先前开发的酸化剂方法用于在恒定pH下进行显式溶剂分子动力学模拟(J. Chem。Phys. 2001, 114, 9706)应用于多功能化合物，即1,4-二氨基丁烷和脱赖氨酸肽。采用酸碱法对1,4-二氨基丁烷在不同pH下的滴定行为进行了一系列模拟研究。该方法至少在一定程度上解释了位点-位点耦合，并在半个pK单位内再现了化合物的实验pK(a)值，尽管模拟显示质子化状态变量的采样不足。在第二步中，通过研究a -螺旋脱氨酸肽的pH依赖性稳定性来测试酸碱法解释溶液pH与生物分子结构和动力学之间相关性的能力。为此，在不同的pH值下进行了4次32-ns恒pH模拟。结果与完全质子化或完全去质子化肽的标准分子动力学模拟结果以及（相对较长的）聚赖氨酸肽的实验数据进行了比较。与实验结果一致，在高ph条件下，肽主要保持a -螺旋构象，但在低ph条件下变得无序。该肽的螺旋圈过渡pH值在9.5 ~ 10.3之间，与聚赖氨酸的实验值（10.3）很好地吻合。恒定ph模拟还证明了特定赖氨酸侧链的质子化与主氢键的局部损失和部分肽展开之间的相关性，这两种影响主要发生在肽的c端区域。
The acidostat method previously developed for performing explicit-solvent molecular dynamics simulations at constant pH (J. Chem. Phys. 2001, 114, 9706) is applied to polyfunctional compounds, namely 1,4-diaminobutane and a decalysine peptide. The titration behavior of 1,4-diaminobutane is investigated by performing a series of simulations at different pH, using the acidostat method. The method accounts at least to some extent for site-site coupling and reproduces the experimental pK(a) values of the compound within half a pK unit, although the simulations reveal insufficient sampling of the protonation- state variables. In a second step, the ability of the acidostat method to account for correlations between the solution pH and the structure and dynamics of a biomolecule is tested by studying the pH-dependent stability of an a.-helical decalysine peptide. To this end, four 32-ns constant-pH simulations at different pH values are performed. The results are compared to those of standard molecular dynamics simulations of a fully protonated or a fully deprotonated peptide, and to experimental data on (comparatively longer) polylysine peptides. In agreement with experiment, the peptide predominantly remains in an a.-helical conformation under high-pH conditions, but becomes disordered under low-pH conditions. The helix-coil transition pH for the peptide is found to be between 9.5 and 10.3, in good agreement with the experimental value for polylysine (10.3). The constant-pH simulations also evidence a correlation between the protonation of specific lysine side chains and the local loss of backbone hydrogen bonds and partial peptide unfolding, both effects occurring predominantly in the C-terminal region of the peptide.