Physics Department T38, Technical University of Munich, 85748 Garching, Germany.
Physics Department T38, Technical University of Munich, 85748 Garching, Germany
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2021263118.
The sequence-dependent structure and deformability of DNA play a major role for binding of proteins and regulation of gene expression. So far, most efforts to model DNA flexibility are based on unimodal harmonic stiffness models at base-pair resolution. However, multimodal behavior due to distinct conformational substates also contributes significantly to the conformational flexibility of DNA. Moreover, these local substates are correlated to their nearest-neighbor substates. A description for DNA elasticity which includes both multimodality and nearest-neighbor coupling has remained a challenge, which we solve by combining our multivariate harmonic approximation with an Ising model for the substates. In a series of applications to DNA fluctuations and protein-DNA complexes, we demonstrate substantial improvements over the unimodal stiffness model. Furthermore, our multivariate Ising model reveals a mechanical destabilization for adenine (A)-tracts to undergo nucleosome formation. Our approach offers a wide range of applications to determine sequence-dependent deformation energies of DNA and to investigate indirect readout contributions to protein-DNA recognition.
DNA 的序列依赖性结构和可变形性对于蛋白质结合和基因表达调控起着重要作用。到目前为止，大多数对 DNA 柔性进行建模的工作都是基于碱基对分辨率的单峰谐刚度模型。然而，由于不同构象亚稳态的多峰行为也对 DNA 的构象柔性有很大的贡献。此外，这些局部亚稳态与它们最近的邻居亚稳态相关。包括多峰性和最近邻耦合的 DNA 弹性描述一直是一个挑战，我们通过将我们的多变量谐逼近与亚稳态的伊辛模型相结合来解决这个问题。在一系列对 DNA 波动和蛋白质-DNA 复合物的应用中，我们证明了与单峰刚度模型相比有了显著的改进。此外，我们的多变量伊辛模型揭示了腺嘌呤（A）-链经历核小体形成的机械不稳定性。我们的方法提供了广泛的应用，以确定 DNA 的序列依赖性变形能，并研究间接读出对蛋白质-DNA 识别的贡献。
