Molecular simulation of conformational transitions in biomolecules using a combination of structure-based potential and empirical valence bond theory
Molecular simulation of conformational transitions in biomolecules using a combination of structure-based potential and empirical valence bond theory
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DOI：
10.1039/b917109f
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Varnai, Peter
中科院分区：
文献类型：
--
作者：
de Marco, Giuseppe;Varnai, Peter
生物大分子的功能本质上与其复杂的构象行为有关。由于这种复杂性，相应的势能景观包含多个最小值。初始状态和最终状态之间的一些中间结构可以通过实验技术来表征。计算机模拟可以探索各个状态的动态，并将它们结合在一起以使整个过程合理化。在这里，我们展示了实验结构可以用于 de。简单而准确的基于原子结构的势（SBP）描述个体构象状态。然后可以使用经验价键 (EVB) 模型将这些单独的状态耦合起来。整个能量景观可以轻松参数化，以重现可用的动力学和热力学数据。我们通过应用 EVB-SBP 方法研究 B-DNA 中的碱基翻转来说明该过程。简单的 SBP 可以重现通过使用更精细的力场模拟获得的结构系综。伞采样与一般能隙反应坐标相结合使我们能够有效地研究替代分子途径。我们发现碱基旋转通过 B-DNA 的两个凹槽进行，并且明显偏爱主凹槽路径。我们还发现了一种不寻常的高能旁路中间体，如果碱基关闭过程是从顺碱基启动的，则可能会出现这种中间体。
The functions of biological macromolecules are inherently linked to their complex conformational behaviour. As a consequence of this complexity, the corresponding potential energy landscapes encompass multiple minima. Some of the intermediate structures between initial and final states can be characterized by experimental techniques. Computer simulations can explore the dynamics of individual states and bring these together to rationalize the overall process. Here, we show that the experimental structures can be exploited to de. ne simple yet accurate atomistic structure-based potentials (SBP) that describe individual conformational states. These individual states can then be coupled by using the empirical valence bond (EVB) model. The overall energy landscape can easily be parameterised to reproduce available kinetic and thermodynamic data. We illustrate the procedure by applying the EVB-SBP method to study base flipping in B-DNA. Simple SBP is shown to reproduce structural ensembles obtained by using more refined force field simulations. Umbrella sampling in conjunction with the general energy gap reaction coordinate enables us to study alternative molecular pathways efficiently. We find that base rotation takes place via both grooves of the B-DNA with a marked preference for the major groove pathway. We also identify an unusual high-energy off-pathway intermediate that may appear if the base closing process is initiated from a syn base.