Atomistic understanding of kinetic pathways for single base-pair binding and unbinding in DNA
Atomistic understanding of kinetic pathways for single base-pair binding and unbinding in DNA
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DOI：
10.1073/pnas.2036378100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Chakraborty, AK
中科院分区：
文献类型：
--
作者：
Hagan, MF;Dinner, AR;Chakraborty, AK
我们结合自由能计算和分子动力学来阐明DNA碱基对结合和解除结合的原子细节机制。具体来说，过渡路径采样用于克服与传统技术相关的计算限制，以获取显式水中3-bp低聚物中末端胞嘧啶翻转的许多轨迹。与伞式采样得到的自由能投影相比较，揭示了将真正的动态过渡态与稳定的反应物和生成物态分开的四个坐标。解键过程通过两种性质不同的途径进行：一种是翻转的碱基在解键之前破坏分子内氢键，另一种是同时破坏两种相互作用。通路上和通路外的中间体都被观察到。讨论了结果与基于dna的生物传感器的粗粒度模型之间的关系。
We combine free-energy calculations and molecular dynamics to elucidate a mechanism for DNA base-pair binding and unbinding in atomic detail. Specifically, transition-path sampling is used to overcome computational limitations associated with conventional techniques to harvest many trajectories for the flipping of a terminal cytosine in a 3-bp oligomer in explicit water. Comparison with free-energy projections obtained with umbrella sampling reveals four coordinates that separate true dynamic transition states from stable reactant and product states. Unbinding proceeds via two qualitatively different pathways: one in which the flipping base breaks its intramolecular hydrogen bonds before it unstacks and another in which it ruptures both sets of interactions simultaneously. Both on- and off-pathway intermediates are observed. The relation of the results to coarse-grained models for DNA-based biosensors is discussed.