Motional timescale predictions by molecular dynamics simulations: case study using proline and hydroxyproline sidechain dynamics.
Motional timescale predictions by molecular dynamics simulations: case study using proline and hydroxyproline sidechain dynamics.
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DOI：
10.1002/prot.24350
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发表时间：
2014-02
影响因子：
2.9
通讯作者：
Lanigan, Rachel M.
中科院分区：
文献类型：
--
作者：
Aliev, Abil E.;Kulke, Martin;Khaneja, Harmeet S.;Chudasama, Vijay;Sheppard, Tom D.;Lanigan, Rachel M.
我们提出了一种新的力场优化的方法，其目的是在再现动力学特性，使用生物分子MD模拟，除了改进预测的运动平均结构特性可从实验中获得。作为动力学拟合的实验数据来源，我们使用骨架和侧链碳的13 C NMR自旋-晶格弛豫时间T1，这使得可以确定整体分子和分子内运动的相关时间。对于结构配件，我们使用NMR J耦合的运动平均实验值。脯氨酸残基及其衍生物4-羟脯氨酸具有相对简单的环状结构和侧链动力学的评估的新方法在这项工作中被选择。最初，网格搜索和简化MD模拟确定了大量的参数集，同样适合实验J耦合。使用力常数和相关时间之间的Arrhenius型关系，分析了一系列参数集的可用MD数据，以预测最能再现侧链动力学实验时间尺度的力常数的值。新力场（称为AMBER 99 SB-ILDNP）对NMR J耦合和相关时间的验证表明，与原始力场相比，在再现结构和动力学特性方面有了一致和显着的改进。结果表明，匹配运动的实验时间尺度和运动平均特性是力场参数优化的有效途径。这种综合方法不限于环状残基，并且可以扩展到其他氨基酸残基以及主链。Proteins 2014; 82：195-215.© 2013 Wiley Periodicals，Inc.
We propose a new approach for force field optimizations which aims at reproducing dynamics characteristics using biomolecular MD simulations, in addition to improved prediction of motionally averaged structural properties available from experiment. As the source of experimental data for dynamics fittings, we use 13C NMR spin-lattice relaxation times T1 of backbone and sidechain carbons, which allow to determine correlation times of both overall molecular and intramolecular motions. For structural fittings, we use motionally averaged experimental values of NMR J couplings. The proline residue and its derivative 4-hydroxyproline with relatively simple cyclic structure and sidechain dynamics were chosen for the assessment of the new approach in this work. Initially, grid search and simplexed MD simulations identified large number of parameter sets which fit equally well experimental J couplings. Using the Arrhenius-type relationship between the force constant and the correlation time, the available MD data for a series of parameter sets were analyzed to predict the value of the force constant that best reproduces experimental timescale of the sidechain dynamics. Verification of the new force-field (termed as AMBER99SB-ILDNP) against NMR J couplings and correlation times showed consistent and significant improvements compared to the original force field in reproducing both structural and dynamics properties. The results suggest that matching experimental timescales of motions together with motionally averaged characteristics is the valid approach for force field parameter optimization. Such a comprehensive approach is not restricted to cyclic residues and can be extended to other amino acid residues, as well as to the backbone. Proteins 2014; 82:195–215. © 2013 Wiley Periodicals, Inc.
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