The relative helix and hydrogen bond stability in the B domain of protein A as revealed by integrated tempering sampling molecular dynamics simulation
The relative helix and hydrogen bond stability in the B domain of protein A as revealed by integrated tempering sampling molecular dynamics simulation
复制标题
集成回火采样分子动力学模拟揭示蛋白质 A B 结构域中的相对螺旋和氢键稳定性
DOI：
10.1063/1.3630127
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发表时间：
2011-10-07
影响因子：
4.4
通讯作者：
Gao, Yi Qin
中科院分区：
文献类型：
--
作者：
Shao, Qiang;Gao, Yi Qin
使用集成回火采样方法对蛋白质 A 的野生型 B 结构域 (BdpA) 的折叠进行了分子动力学模拟。从随机和拉伸结构开始，这些模拟使我们能够频繁地将这种蛋白质折叠成类似天然的结构，实现非常小的主链（1.7埃）和所有重原子均方根偏差（2.6埃）。因此，这里使用的方法提高了分子动力学模拟构型采样和热力学表征的效率。尽管绝对稳定性的计算与实验之间存在不一致，但由于力场参数的限制，计算出的螺旋稳定性顺序（H3 > H2 > H1）与单独螺旋的实验确定的顺序一致。研究发现，BdpA 的最低自由能折叠途径始于从完全伸展 (E) 状态的无屏障和非合作结构塌陷，从而导致生理上未折叠 (P) 状态，该状态由多个稳定结构组成，几乎没有形成天然螺旋间疏水相互作用。在P状态下，只有H3是完全结构化的。折叠 (F) 状态下 H1（以及较小程度上的 H2）的最终形成需要螺旋间疏水接触的堆积。此外，还发现主链氢键的稳定性受到其相对于螺旋间疏水核心的位置的显着影响。随着温度升高，暴露于溶剂中的氢键的稳定性趋于增加，而埋藏在疏水核内的氢键的稳定性趋于降低。最后，我们讨论了这项研究对蛋白质一般折叠机制的影响。 (C) 2011 年美国物理研究所。 [doi:10.1063/1.3630127]
Molecular dynamics simulations using the integrated tempering sampling method were performed for the folding of wild-type B domain of protein A (BdpA). Starting from random and stretched structures, these simulations allow us to fold this protein into the native-like structure frequently, achieving very small backbone (1.7 angstrom) and all heavy-atom root-mean-square deviation (2.6 angstrom). Therefore, the method used here increases the efficiency of configuration sampling and thermodynamics characterization by molecular dynamics simulation. Although inconsistency exists between the calculation and experiments for the absolute stabilities, as a limitation of the force field parameters, the calculated order of helix stability (H3 > H2 > H1) is consistent with that determined by experiments for individual separate helices. The lowest free energy folding pathway of BdpA was found to start with a barrierless and non-cooperative structural collapse from the entirely extended (E) state, which leads to a physiologically unfolded (P) state consisting of multiple stable structures with few native inter-helical hydrophobic interactions formed. In the P state, only H3 is fully structured. The final formation of H1 (and to a lesser extent, H2) in the folded (F) state requires the packing of the inter-helical hydrophobic contacts. In addition, it was found that stabilities of backbone hydrogen bonds are significantly affected by their positions relative to the inter-helical hydrophobic core. As temperature increases, the stability of the hydrogen bonds exposed to the solvent tends to increase while that of the hydrogen bonds buried within the hydrophobic core decreases. Finally, we discuss implications of this study on the general folding mechanism of proteins. (C) 2011 American Institute of Physics. [doi:10.1063/1.3630127]