Biomolecular force fields optimized for globular proteins fail to properly reproduce properties of intrinsically disordered proteins. In particular, parameters of the water model need to be modified to improve applicability of the force fields to both ordered and disordered proteins. Here, we compared performance of force fields recommended for intrinsically disordered proteins in molecular dynamics simulations of three proteins differing in the content of ordered and disordered regions (two proteins consisting of a well-structured domain and of a disordered region with and without a transient helical motif and one disordered protein containing a region of increased helical propensity). The obtained molecular dynamics trajectories were used to predict measurable parameters, including radii of gyration of the proteins and chemical shifts, residual dipolar couplings, paramagnetic relaxation enhancement, and NMR relaxation data of their individual residues. The predicted quantities were compared with experimental data obtained within this study or published previously. The results showed that the NMR relaxation parameters, rarely used for benchmarking, are particularly sensitive to the choice of force-field parameters, especially those defining the water model. Interestingly, the TIP3P water model, leading to an artificial structural collapse, also resulted in unrealistic relaxation properties. The TIP4P-D water model, combined with three biomolecular force-field parameters for the protein part, significantly improved reliability of the simulations. Additional analysis revealed only one particular force field capable of retaining the transient helical motif observed in NMR experiments. The benchmarking protocol used in our study, being more sensitive to imperfections than the commonly used tests, is well suited to evaluate the performance of newly developed force fields.

中文翻译：

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包含结构化和内在无序区域的蛋白质的力场选择

针对球状蛋白质优化的生物分子力场无法正确再现内在无序蛋白质的特性。特别是，需要修改水模型的参数以提高力场对有序和无序蛋白质的适用性。在这里，我们比较了在分子动力学模拟中推荐用于内在无序蛋白质的力场的性能，这些蛋白质在有序和无序区域的含量上有所不同（两种蛋白质由结构良好的结构域和无序区域组成，有和没有瞬态螺旋基序和一种包含螺旋倾向增加区域的无序蛋白质）。获得的分子动力学轨迹用于预测可测量的参数，包括蛋白质的回转半径和化学位移，残余偶极耦合、顺磁弛豫增强和它们各个残基的 NMR 弛豫数据。预测的数量与本研究中获得的或之前发表的实验数据进行了比较。结果表明，很少用于基准测试的 NMR 弛豫参数对力场参数的选择特别敏感，尤其是那些定义水模型的参数。有趣的是，导致人工结构坍塌的 TIP3P 水模型也导致了不切实际的松弛特性。TIP4P-D 水模型与蛋白质部分的三个生物分子力场参数相结合，显着提高了模拟的可靠性。额外的分析表明，只有一种特定的力场能够保留在 NMR 实验中观察到的瞬态螺旋基序。我们研究中使用的基准协议比常用的测试对缺陷更敏感，非常适合评估新开发的力场的性能。