An Improved Reaction Coordinate for Nucleic Acid Base Flipping Studies.
An Improved Reaction Coordinate for Nucleic Acid Base Flipping Studies.
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DOI：
10.1021/ct9001575
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发表时间：
2009-11-10
影响因子：
5.5
通讯作者：
Simmerling C
中科院分区：
文献类型：
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作者：
Song K;Campbell AJ;Bergonzo C;de Los Santos C;Grollman AP;Simmerling C
碱基翻转是许多酶利用的一种常见策略，以获得双链DNA中核酸碱基的官能团，这些官能团受到DNA主链和与其伙伴碱基的氢键的保护。几项x射线晶体学研究揭示了核苷酸与酶结合的翻转构象。然而，对碱基翻转过程本身所知甚少，更不用说酶的作用了。计算研究采用伞式采样法，用伪二面角表示反应坐标，得到了碱翻转过程的自由能分布。在这项研究中，我们使用了一个不受约束的轨迹，其中翻转的碱基自发地重新插入到螺旋中，以评估和改进先前定义的伪二面角。我们改进的伪二面角使用了新的原子选择，提高了约束的数值稳定性，并且与模拟中观察到的翻转程度提供了更好的相关性。此外，基于使用不同反应坐标生成的PMF的比较，我们观察到翻转PMF轮廓的形状强烈依赖于反应坐标的定义，即使对于相同的数据集也是如此。
Base flipping is a common strategy utilized by many enzymes to gain access to the functional groups of nucleic acid bases in duplex DNA which are otherwise protected by the DNA backbone and hydrogen bonding with their partner bases. Several X-ray crystallography studies have revealed flipped conformations of nucleotides bound to enzymes. However, little is known about the base flipping process itself, even less about the role of the enzymes. Computational studies have used umbrella sampling to elicit the free energy profile of the base flipping process using a pseudo-dihedral angle to represent the reaction coordinate. In this study we have used an unrestrained trajectory in which a flipped base spontaneously reinserted into the helix in order to evaluate and improve the previously defined pseudo-dihedral angle. Our modified pseudo-dihedral angles use a new atom selection to improve the numerical stability of the restraints and also provide better correlation to the extent of flipping observed in simulations. Furthermore, based on the comparison of PMFs generated using different reaction coordinates, we observed that the shape of a flipping PMF profile is strongly dependent on the definition of the reaction coordinate, even for the same data set.