Conformational Preferences of an Intrinsically Disordered Protein Domain: A Case Study for Modern Force Fields
Conformational Preferences of an Intrinsically Disordered Protein Domain: A Case Study for Modern Force Fields
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DOI：
10.1021/acs.jpcb.0c08702
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发表时间：
2021-01-14
影响因子：
3.3
通讯作者：
Schaefer, Lars, V
中科院分区：
文献类型：
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作者：
Gopal, Srinivasa M.;Wingbermuehle, Sebastian;Schaefer, Lars, V
本质无序蛋白质(IDPs)的分子模拟具有挑战性，因为它们需要采样非常大量的相关构象，对应于平面自由能景观中的大量浅极小值。然而，在具有约束力的伙伴的存在下，IDP的自由能格局可能被几个深极小值所主导。这一特点对描述分子相互作用的力场的准确性提出了很高的要求。这里，作为一个在溶液中是非结构化的但在与结构化相互作用伙伴结合时折叠的IDP的模型系统，研究了c-Myb的反式激活结构域在未结合(自由)形式和结合到KIX结构域时的情况。对六个现代生物分子力场进行了系统的测试和比较，比较了它们描述IdP结构系综的能力。本研究中包括的蛋白质力场/水模型组合是：Amber ff99Sb-Disp与其相应的水模型TIP4P-D，CHARMM36m与TIP3P，ff15ipq与SPC/E-b，ff99Sb*-ILDNP与TIP3P和TIP4P-D，以及FB15与TIP3P-FB水。将REST2增强采样模拟的结果与实验的CD光谱和二次化学位移进行比较，表明ff99Sb-Disp力场能够真实地捕捉到自由c-Myb的宽广和温和的螺旋结构系综。CHARMM36m、ff99Sb*-ILDNP与TIP4P-D水和FB15产生的结构系综也是温和的螺旋结构；然而，这些力场中的每一个都可以分配到c-Myb残基的一个特定子集，模拟不能再现实验的二级化学位移。此外，对KIX/c-Myb复合体的微秒级MD模拟表明，大多数力场都保持了c-Myb在复合体中稳定的螺旋折叠。尽管如此，所有力场都预测了KIX/c-Myb复合体界面，该界面与核磁共振提供的结构略有不同，因为在模拟中超过了KIX和c-Myb之间的几个NOE派生距离。综上所述，ff99Sb-Disp力场首先是CHARMM36m，ff99Sb*-ILDNP加上TIP4P-D水，以及FB15可以作为未来模拟研究KIX/c-Myb复合物的耦合折叠和结合机制的合适选择，也可能是其他IDPs的模拟研究。
Molecular simulations of intrinsically disordered proteins (IDPs) are challenging because they require sampling a very large number of relevant conformations, corresponding to a multitude of shallow minima in a flat free energy landscape. However, in the presence of a binding partner, the free energy landscape of an IDP can be dominated by few deep minima. This characteristic imposes high demands on the accuracy of the force field used to describe the molecular interactions. Here, as a model system for an IDP that is unstructured in solution but folds upon binding to a structured interaction partner, the transactivation domain of c-Myb was studied both in the unbound (free) form and when bound to the KIX domain. Six modern biomolecular force fields were systematically tested and compared in terms of their ability to describe the structural ensemble of the IDP. The protein force field/water model combinations included in this study are AMBER ff99SB-disp with its corresponding water model that was derived from TIP4P-D, CHARMM36m with TIP3P, ff15ipq with SPC/E-b, ff99SB*-ILDNP with TIP3P and TIP4P-D, and FB15 with TIP3P-FB water. Comparing the results from REST2-enhanced sampling simulations with experimental CD spectra and secondary chemical shifts reveals that the ff99SB-disp force field can realistically capture the broad and mildly helical structural ensemble of free c-Myb. The structural ensembles yielded by CHARMM36m, ff99SB*-ILDNP together with TIP4P-D water, and FB15 are also mildly helical; however, each of these force fields can be assigned a specific subset of c-Myb residues for which the simulations could not reproduce the experimental secondary chemical shifts. In addition, microsecond-timescale MD simulations of the KIX/c-Myb complex show that most force fields used preserve a stable helix fold of c-Myb in the complex. Still, all force fields predict a KIX/c-Myb complex interface that differs slightly from the structures provided by NMR because several NOE-derived distances between KIX and c-Myb were exceeded in the simulations. Taken together, the ff99SB-disp force field in the first place but also CHARMM36m, ff99SB*-ILDNP together with TIP4P-D water, and FB15 can be suitable choices for future simulation studies of the coupled folding and binding mechanism of the KIX/c-Myb complex and potentially also other IDPs.