Systematic Differences between Current Molecular Dynamics Force Fields To Represent Local Properties of Intrinsically Disordered Proteins
Systematic Differences between Current Molecular Dynamics Force Fields To Represent Local Properties of Intrinsically Disordered Proteins
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当前分子动力学力场之间的系统差异代表本质无序蛋白质的局部特性
DOI：
10.1021/acs.jpcb.0c10078
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Brüschweiler, Rafael
中科院分区：
文献类型：
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作者：
Yu, Lei;Li, Da-Wei;Brüschweiler, Rafael
结构生物学中固有无序蛋白质和蛋白质区域的普遍存在促使了分子动力学力场的发展，以更真实地描述这种系统。我们使用天然水环境中本质无序蛋白质α-突触核蛋白和淀粉样蛋白-β的实验核磁共振骨架标量3 J耦合常数作为指标，比较了四种最近的MD力场的性能，即AMBER ff 14 SB、CHARMM C36 m、AMBER ff 99 SB-disp和AMBER ff 99 SBnmr 2，通过将多肽划分为重叠的七肽系列，对这些七肽进行了累计总计276 μs的MD模拟。结果表明，在各个残留水平上，不同力场之间存在实质性差异。除ff 99 SBnmr 2外，由于β-构象的代表性不足和α-或PPII构象的代表性过高，力场系统地低估了标量3 J（HN，Hα）-耦合。该研究表明，在现代MD力场中纳入线圈库信息，如此处所示的ff 99 SBnmr 2，提供了大幅改善的性能和更真实的IDP局部骨架二面角采样，这反映在计算的标量3 J（HN，Hα）耦合的良好精度上，误差小于0.5 Hz。这样的力场将能够更好地理解结构动力学和热力学如何影响IDP功能。虽然这里使用的七肽的基础上的方法不允许潜在的分子内长程相互作用的评估，其计算的负担能力允许收敛良好的模拟，可以很容易地并行化。这应该使内在的障碍，观察到的MD模拟多肽与实验scalarJ-耦合广泛适用的定量验证。
The prevalence of intrinsically disordered proteins (IDPs) and protein regions in structural biology has prompted the recent development of molecular dynamics (MD) force fields for the more realistic representations of such systems. Using experimental nuclear magnetic resonance backbone scalar3J-coupling constants of the intrinsically disordered proteins α-synuclein and amyloid-β in their native aqueous environment as a metric, we compare the performance of four recent MD force fields, namely, AMBER ff14SB, CHARMM C36m, AMBER ff99SB-disp, and AMBER ff99SBnmr2, by partitioning the polypeptides into an overlapping series of heptapeptides for which a cumulative total of 276 μs MD simulations were performed. The results show substantial differences between the different force fields at the individual residue level. Except for ff99SBnmr2, the force fields systematically underestimate the scalar3J(HN,Hα)-couplings due to an underrepresentation of β-conformations and an overrepresentation of either α- or PPIIconformations. The study demonstrates that the incorporation of coil library information in modern MD force fields, as shown here for ff99SBnmr2, provides substantially improved performance and more realistic sampling of the local backbone dihedral angles of IDPs as reflected by the good accuracy of the computed scalar3J(HN,Hα)-couplings with less than 0.5 Hz error. Such force fields will enable a better understanding of how structural dynamics and thermodynamics influence the IDP function. Although the methodology based on heptapeptides used here does not allow the assessment of potential intramolecular long-range interactions, its computational affordability permits well-converged simulations that can be easily parallelized. This should make the quantitative validation of intrinsic disorder observed in MD simulations of polypeptides with experimental scalarJ-couplings widely applicable.