Free energy landscape of protein folding in water: Explicit vs. implicit solvent
Free energy landscape of protein folding in water: Explicit vs. implicit solvent
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DOI：
10.1002/prot.10483
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发表时间：
2003-11
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通讯作者：
R. Zhou
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文献类型：
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作者：
R. Zhou
广义玻恩（GB）连续溶剂模型可以说是蛋白质折叠和蛋白质结构预测模拟中使用最广泛的隐式溶剂模型;然而，该模型在这些大规模模拟中的表现如何仍然是一个悬而未决的问题。本研究以蛋白质G C末端的β-发夹结构为例，探讨了各种GB模型的折叠自由能景观，并将结果与显式溶剂模拟和实验进行了比较。所有的自由能景观得到广泛的构象空间采样与高度并行的副本交换方法。由于溶剂化模型参数与力场之间存在强耦合关系，因此本研究考察并比较了五种不同的力场/溶剂化模型组合，即显式溶剂模型：OPLSAA/SPC模型，以及隐式溶剂模型：OPLSAA/SGB（Surface GB）、AMBER 94/GBSA（GB with Solvent Dissolvable Surface Area）、AMBER 96/GBSA和AMBER 99/GBSA。令人惊讶的是，我们发现，从隐式溶剂模型的自由能景观是完全不同的显式溶剂模型。除AMBER 96/GBSA外，所有其他隐式溶剂模型都发现了最低的自由能状态而不是自然状态。所有隐式溶剂模型都显示带电残基之间的错误盐桥效应，特别是在OPLSAA/SGB模型中，其中过强的盐桥效应导致非天然结构的超重，其中一个疏水残基F52从疏水核中排出，以形成更好的盐桥。另一方面，AMBER 94/GBSA和AMBER 99/GBSA模型都将β-发夹转化为α-螺旋，并且α-螺旋含量远远高于先前使用AMBER 94（AMBER 94/TIP 3 P）进行的显式溶剂模拟中报道的α-螺旋。只有AMBER 96/GBSA显示出合理的自由能图谱，其自由能结构最低，尽管D47和K50之间存在错误的盐桥。详细的结果，自由能等高线图，最低自由能结构，分布的天然接触，α-螺旋内容在折叠过程中，NOE与NMR的比较，和温度依赖性的报告和讨论的所有五个模型。Proteins 2003.© 2003 Wiley利斯公司
The Generalized Born (GB) continuum solvent model is arguably the most widely used implicit solvent model in protein folding and protein structure prediction simulations; however, it still remains an open question on how well the model behaves in these large‐scale simulations. The current study uses the β‐hairpin from C‐terminus of protein G as an example to explore the folding free energy landscape with various GB models, and the results are compared to the explicit solvent simulations and experiments. All free energy landscapes are obtained from extensive conformation space sampling with a highly parallel replica exchange method. Because solvation model parameters are strongly coupled with force fields, five different force field/solvation model combinations are examined and compared in this study, namely the explicit solvent model: OPLSAA/SPC model, and the implicit solvent models: OPLSAA/SGB (Surface GB), AMBER94/GBSA (GB with Solvent Accessible Surface Area), AMBER96/GBSA, and AMBER99/GBSA. Surprisingly, we find that the free energy landscapes from implicit solvent models are quite different from that of the explicit solvent model. Except for AMBER96/GBSA, all other implicit solvent models find the lowest free energy state not the native state. All implicit solvent models show erroneous salt‐bridge effects between charged residues, particularly in OPLSAA/SGB model, where the overly strong salt‐bridge effect results in an overweighting of a non‐native structure with one hydrophobic residue F52 expelled from the hydrophobic core in order to make better salt bridges. On the other hand, both AMBER94/GBSA and AMBER99/GBSA models turn the β‐hairpin in to an α‐helix, and the α‐helical content is much higher than the previously reported α‐helices in an explicit solvent simulation with AMBER94 (AMBER94/TIP3P). Only AMBER96/GBSA shows a reasonable free energy landscape with the lowest free energy structure the native one despite an erroneous salt‐bridge between D47 and K50. Detailed results on free energy contour maps, lowest free energy structures, distribution of native contacts, α‐helical content during the folding process, NOE comparison with NMR, and temperature dependences are reported and discussed for all five models. Proteins 2003. © 2003 Wiley‐Liss, Inc.