Molecular Dynamics-Assisted Optimization of Protein NMR Relaxation Analysis.
Molecular Dynamics-Assisted Optimization of Protein NMR Relaxation Analysis.
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DOI：
10.1021/acs.jctc.1c01165
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发表时间：
2022-04-12
影响因子：
5.5
通讯作者：
LeMaster, David M.
中科院分区：
文献类型：
--
作者：
Anderson, Janet S.;Hernandez, Griselda;LeMaster, David M.
球状蛋白中可移动残基的核磁共振弛豫分析对实验拟合的内部自相关函数的形式很敏感，该函数用于表示该运动。不同的阶数参数表示可以精确拟合相同的15N R1、R2和异核NOE测量集，但对潜在的自相关函数的预测却存在显著差异，这表明这些实验松弛数据在评估哪种阶数参数表示提供最现实的物理预测方面存在不足。分子动力学模拟提供了一种无与伦比的能力来区分不同阶参数表示，以评估哪种表示可以最准确地模拟各种物理上真实的自相关函数。采用目前常用的6个AMBER和CHARMM力场计算泛素骨架H-N键向量的自相关函数，作为操作测试集。优化的时间常数约束三指数（TCCT）表示法明显优于广泛使用的（Sf2,τs,S2）扩展Lipari-Szabo表示法和更密切相关的（Sf2,SH2, SN2） Larmor频率选择表示法。600和900 MHz 1H的TCCT表示的优化收敛到相同的参数化。较高的磁场对可移动酰胺的自相关函数的反向预测产生了系统性的较大偏差，这表明在分析缺乏较慢（~ ms）交换线展宽效应的酰胺时，多场测量几乎没有额外的好处。实验15N弛豫数据在预测ps-ns时间框架内泛素主链构象动力学方面能有效区分不同的力场。早期的AMBER 99SB和CHARMM27力场低估了发生在这个时间框架内的主链动力学的规模，而AMBER 14SB对泛素的高移动c端残基提供了最一致的预测。
NMR relaxation analysis of the mobile residues in globular proteins is sensitive to the form of the experimentally fitted internal autocorrelation function, which is used to represent that motion. Different order parameter representations can precisely fit the same set of 15N R1, R2, and heteronuclear NOE measurements while yielding significantly divergent predictions of the underlying autocorrelation functions, indicating the insufficiency of these experimental relaxation data for assessing which order parameter representation provides the most physically realistic predictions. Molecular dynamics simulations offer an unparalleled capability for discriminating among different order parameter representations to assess which representation can most accurately model a wide range of physically realistic autocorrelation functions. Six currently utilized AMBER and CHARMM force fields were applied to calculate autocorrelation functions for the backbone H–N bond vectors of ubiquitin as an operational test set. An optimized time constant-constrained triexponential (TCCT) representation was shown to markedly outperform the widely used (Sf2,τs,S2) extended Lipari–Szabo representation and the more closely related (Sf2,SH2, SN2) Larmor frequency-selective representation. Optimization of the TCCT representation at both 600 and 900 MHz 1H converged to the same parameterization. The higher magnetic field yielded systematically larger deviations in the back-prediction of the autocorrelation functions for the mobile amides, indicating little added benefit from multiple field measurements in analyzing amides that lack slower (∼ms) exchange line-broadening effects. Experimental 15N relaxation data efficiently distinguished among the different force fields with regard to their prediction of ubiquitin backbone conformational dynamics in the ps–ns time frame. While the earlier AMBER 99SB and CHARMM27 force fields underestimate the scale of backbone dynamics, which occur in this time frame, AMBER 14SB provided the most consistent predictions for the well-averaged highly mobile C-terminal residues of ubiquitin.
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影响因子：
16.6
作者：
Liu, Zhu;Zhang, Wei-Ping;Xing, Qiong;Ren, Xuefeng;Liu, Maili;Tang, Chun
通讯作者：
Tang, Chun
影响因子：
15
作者：
Hall, Jennifer B.;Fushman, David
通讯作者：
Fushman, David
影响因子：
2.9
作者：
ISHIMA, R;NAGAYAMA, K
通讯作者：
NAGAYAMA, K
影响因子：
2.7
作者：
Buevich, AV;Shinde, UP;Baum, J
通讯作者：
Baum, J
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.