Van Wynsberghe Adam W, Cui Qiang
Graduate Program in Biophysics and Department of Chemistry and Theoretical Chemistry Institute, University of Wisconsin, Madison, WI, USA.
Biophys J. 2005 Nov;89(5):2939-49. doi: 10.1529/biophysj.105.065664. Epub 2005 Aug 12.
More than two decades of different types of mode analyses has shown that these techniques can be useful in describing large-scale motions in protein systems. A number of mode analyses are available and include quasiharmonics, classical normal mode, block normal mode, and the elastic network model. Each of these methods has been validated for protein systems and this variety allows researchers to choose the technique that gives the best compromise between computational cost and the level of detail in the calculation. These same techniques have not been systematically tested for nucleic acid systems, however. Given the differences in interactions and structural features between nucleic acid and protein systems, the validity of these techniques in the protein regime cannot be directly translated into validity in the nucleic acid realm. In this work, we investigate the usefulness of the above mode analyses as applied to two RNA systems, i.e., the hammerhead ribozyme and a guanine riboswitch. We show that classical normal-mode analysis can match the magnitude and direction of residue fluctuations from the more detailed, anharmonic technique, quasiharmonic analysis of a molecular dynamics trajectory. The block normal-mode approximation is shown to hold in the nucleic acid systems studied. Only the mode analysis at the lowest level of detail, the elastic network model, produced mixed results in our calculations. We present data that suggest that the elastic network model, with the popular parameterization, is not best suited for systems that do not have a close packed structure; this observation also hints at why the elastic network model has been found to be valid for many globular protein systems. The different behaviors of block normal-mode analysis and the elastic network model, which invoke similar degrees of coarse-graining to the dynamics but use different potentials, suggest the importance of applying a heterogeneous potential function in a robust analysis of the dynamics of biomolecules, especially those that are not closely packed. In addition to these comparisons, we briefly discuss insights into the conformational space available to the hammerhead ribozyme.
二十多年来，不同类型的模式分析表明，这些技术在描述蛋白质系统中的大规模运动方面可能很有用。有多种模式分析方法，包括准谐波分析、经典正则模式分析、块正则模式分析和弹性网络模型。这些方法中的每一种都已在蛋白质系统中得到验证，这种多样性使研究人员能够选择在计算成本和计算细节水平之间取得最佳平衡的技术。然而，这些相同的技术尚未在核酸系统中进行系统测试。鉴于核酸和蛋白质系统在相互作用和结构特征方面存在差异，这些技术在蛋白质领域的有效性不能直接转化为在核酸领域的有效性。在这项工作中，我们研究了上述模式分析应用于两个RNA系统（即锤头状核酶和鸟嘌呤核糖开关）的有用性。我们表明，经典正则模式分析能够与来自更详细的非谐技术（分子动力学轨迹的准谐波分析）的残基波动的大小和方向相匹配。在所研究的核酸系统中，块正则模式近似被证明是成立的。在我们的计算中，只有最粗略的模式分析，即弹性网络模型，产生了混合结果。我们提供的数据表明，具有常用参数化的弹性网络模型不太适合没有紧密堆积结构的系统；这一观察结果也暗示了为什么弹性网络模型已被发现对许多球状蛋白质系统有效。块正则模式分析和弹性网络模型的不同行为，它们对动力学采用了相似程度的粗粒化但使用了不同的势函数，这表明在对生物分子动力学进行稳健分析时，应用非均匀势函数的重要性，特别是对于那些没有紧密堆积的生物分子。除了这些比较之外，我们还简要讨论了对锤头状核酶可用构象空间的见解。
