Wang Wei, Ye Wei, Jiang Cheng, Luo Ray, Chen Hai-Feng
State Key Laboratory of Microbial metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Chem Biol Drug Des. 2014 Sep;84(3):253-69. doi: 10.1111/cbdd.12314. Epub 2014 Jul 1.
Intrinsically disordered proteins or intrinsically disordered protein regions comprise a large portion of eukaryotic proteomes (between 35% and 51%). These intrinsically disordered proteins were found to link with cancer and various other diseases. However, widely used additive force field parameter sets are insufficient in quantifying the structural properties of intrinsically disordered proteins. Therefore, we explored to a systematic correction of a base additive force field parameter set (chosen as Amber ff99SBildn) to correct the biases that was first demonstrated in simulations with the base parameter set. Specifically, the φ/ψ distributions of disorder-promoting residues were systematically corrected with the CMAP method. Our simulations show that the CMAP corrected Amber parameter set, termed ff99IDPs, improves the φ/ψ distributions of the disorder-promoting residues with respect to the benchmark data of intrinsically disordered protein structures, with root mean-squared percentage deviation less than 0.15% between the simulation and the benchmark. Our further validation shows that the chemical shifts from the ff99IDPs simulations are in quantitative agreement with those from reported NMR measurements for two tested IDPs, MeV NTAIL , and p53. The predicted residue dipolar couplings also show high correlation with experimental data. Interestingly, our simulations show that ff99IDPs can still be used to model the ordered state when the intrinsically disordered proteins are in complex, in contrast to ff99SBildn that can be applied well only to the ordered complex structures. These findings confirm that the newly proposed Amber ff99IDPs parameter set provides a reasonable tool in further studies of intrinsically disordered protein structures. In addition, our study also shows the importance of considering intrinsically disordered protein structures in general-purposed force field developments for both additive and non-additive models.
内在无序蛋白质或内在无序蛋白质区域占真核生物蛋白质组的很大一部分（35%至51%）。这些内在无序蛋白质被发现与癌症及其他多种疾病相关。然而，广泛使用的加和力场参数集在量化内在无序蛋白质的结构特性方面并不充分。因此，我们探索对一个基础加和力场参数集（选择为Amber ff99SBildn）进行系统校正，以纠正首次在使用基础参数集的模拟中表现出的偏差。具体而言，使用CMAP方法对促进无序的残基的φ/ψ分布进行了系统校正。我们的模拟表明，经CMAP校正的Amber参数集，称为ff99IDPs，相对于内在无序蛋白质结构的基准数据，改善了促进无序的残基的φ/ψ分布，模拟与基准之间的均方根百分比偏差小于0.15%。我们的进一步验证表明，ff99IDPs模拟得到的化学位移与针对两个测试的内在无序蛋白质MeV NTAIL和p53的已报道NMR测量结果在定量上一致。预测的残基偶极耦合也与实验数据显示出高度相关性。有趣的是，我们的模拟表明，当内在无序蛋白质处于复合物中时，ff99IDPs仍可用于对有序状态进行建模，而ff99SBildn仅能很好地应用于有序的复合物结构。这些发现证实，新提出的Amber ff99IDPs参数集为进一步研究内在无序蛋白质结构提供了一个合理的工具。此外，我们的研究还表明，在用于加和模型和非加和模型的通用力场开发中考虑内在无序蛋白质结构的重要性。
