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首页> 外文期刊>BMC Genomics >A theoretical investigation of DNA dynamics and desolvation kinetics for zinc finger proteinZif268
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A theoretical investigation of DNA dynamics and desolvation kinetics for zinc finger proteinZif268

机译：锌指蛋白的DNA动力学和去溶剂化动力学的理论研究

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Background Transcription factors, regulating the expression inventory of a cell, interact with its respective DNA subjugated by a specific recognition pattern, which if well exploited may ensure targeted genome engineering. The mostly widely studied transcription factors are zinc finger proteins that bind to its target DNA via direct and indirect recognition levels at the interaction interface. Exploiting the binding specificity and affinity of the interaction between the zinc fingers and the respective DNA can help in generating engineered zinc fingers for therapeutic applications. Experimental evidences lucidly substantiate the effect of indirect interaction like DNA deformation and desolvation kinetics, in empowering ZFPs to accomplish partial sequence specificity functioning around structural properties of DNA. Exploring the structure-function relationships of the existing zinc finger-DNA complexes at the indirect recognition level can aid in predicting the probable zinc fingers that could bind to any target DNA. Deformation energy, which defines the energy required to bend DNA from its native shape to its shape when bound to the ZFP, is an effect of indirect recognition mechanism. Water is treated as a co-reactant for unfurling the affinity studies in ZFP-DNA binding equilibria that takes into account the unavoidable change in hydration that occurs when these two solvated surfaces come into contact. Results Aspects like desolvation and DNA deformation have been theoretically investigated based on simulations and free energy perturbation data revealing a consensus in correlating affinity and specificity as well as stability for ZFP-DNA interactions. Greater loss of water at the interaction interface of the DNA calls for binding with higher affinity, eventually distorting the DNA to a greater extent accounted by the change in major groove width and DNA tilt, stretch and rise. Conclusion Most prediction algorithms for ZFPs do not account for water loss at the interface. The above findings may significantly affect these algorithms. Further the sequence dependent deformation in the DNA upon complexation with our prototype as well as preference of bases at the 2nd and 3rd position of the repeating triplet provide an absolutely new insight about the indirect interactions undergoing a change that have not been probed yet.
机译：背景转录因子调节细胞的表达量，并通过特定的识别模式与相应的DNA相互作用，如果利用得当，可以确保靶向的基因组工程。研究最广泛的转录因子是锌指蛋白，它们通过相互作用界面上的直接和间接识别水平与靶DNA结合。利用锌指与各个DNA之间相互作用的结合特异性和亲和力可以帮助产生工程化的锌指以用于治疗应用。实验证据清楚地证实了间接相互作用（如DNA变形和去溶剂化动力学）的作用，这使ZFP能够完成围绕DNA结构特性的部分序列特异性功能。在间接识别水平上探索现有锌指-DNA复合物的结构-功能关系可以帮助预测可能与任何靶DNA结合的锌指。变形能是间接识别机制的作用，它定义了将DNA从其天然形状弯曲到与ZFP结合时所需的能量。水被视为一种共反应物，用于展开ZFP-DNA结合平衡中的亲和力研究，该研究考虑到这两个溶剂化表面接触时不可避免的水合变化。结果基于模拟和自由能扰动数据，从理论上研究了去溶剂化和DNA变形等方面，揭示了在亲和力和特异性以及ZFP-DNA相互作用的稳定性相关方面的共识。 DNA相互作用界面上水分的大量流失要求以更高的亲和力进行结合，最终导致DNA更大程度地变形，这是由主要凹槽宽度的变化以及DNA倾斜，伸展和上升引起的。结论大多数ZFP的预测算法都没有考虑界面处的水分流失。以上发现可能会严重影响这些算法。此外，与我们的原型复合后，DNA中依赖序列的变形以及在重复三联体的2 nd 和3 rd 位置碱基的偏好性提供了绝对全新的见解关于正在进行更改的间接交互（尚未进行探讨）。

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