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Abstract：
Recent advances in coarse-grained (CG) computational models for DNA have enabled molecular-level insights into the behavior of DNA in complex multiscale systems. However, most existing CG DNA models are not compatible with CG protein models, limiting their applications for emerging topics such as protein-nucleic acid assemblies. Here, we present a new computationally efficient CG DNA model. We first use experimental data to establish the model\'s ability to predict various aspects of DNA behavior, including melting thermodynamics and relevant local structural properties such as the major and minor grooves. We then employ an all-atom hydropathy scale to define nonbonded interactions between protein and DNA sites, to make our DNA model compatible with an existing CG protein model (HPS-Urry), which is extensively used to study protein phase separation, and show that our new model reasonably reproduces the experimental binding affinity for a prototypical protein-DNA system. To further demonstrate the capabilities of this new model, we simulate a full nucleosome with and without histone tails, on a microsecond time scale, generating conformational ensembles and provide molecular insights into the role of histone tails in influencing the liquid-liquid phase separation (LLPS) of HP1α proteins. We find that histone tails interact favorably with DNA, influencing the conformational ensemble of the DNA and antagonizing the contacts between HP1α and DNA, thus affecting the ability of DNA to promote LLPS of HP1α. These findings shed light on the complex molecular framework that fine-tunes the phase transition properties of heterochromatin proteins and contributes to heterochromatin regulation and function. Overall, the CG DNA model presented here is suitable to facilitate micrometer-scale studies with sub-nm resolution in many biological and engineering applications and can be used to investigate protein-DNA complexes, such as nucleosomes, or LLPS of proteins with DNA, enabling a mechanistic understanding of how molecular information may be propagated at the genome level.
摘要：
DNA粗粒度（CG）计算模型的最新进展使分子水平的见解能够在复杂的多尺度系统中DNA的行为。然而,大多数现有的CGDNA模型与CG蛋白质模型不兼容，将其应用限制在蛋白质-核酸组装等新兴主题中。这里,我们提出了一种新的计算高效的CGDNA模型。我们首先利用实验数据建立模型来预测DNA行为的各个方面,包括熔化热力学和相关的局部结构特性，如主要和次要的凹槽。然后，我们使用全原子亲水量表来定义蛋白质和DNA位点之间的非键合相互作用，为了使我们的DNA模型与现有的CG蛋白模型（HPS-Urry）兼容，广泛用于研究蛋白质相分离，并表明我们的新模型合理地再现了原型蛋白质-DNA系统的实验结合亲和力。为了进一步证明这个新模型的功能，我们模拟了一个有和没有组蛋白尾巴的完整核小体，在微秒的时间尺度上，生成构象集合，并提供对组蛋白尾巴在影响HP1α蛋白的液-液相分离（LLPS）中的作用的分子见解。我们发现组蛋白尾巴与DNA有良好的相互作用，影响DNA的构象集合并拮抗HP1α与DNA之间的接触，从而影响DNA促进HP1αLLPS的能力。这些发现揭示了复杂的分子框架，该框架可以微调异染色质蛋白的相变特性，并有助于异染色质的调节和功能。总的来说,这里介绍的CGDNA模型适用于许多生物和工程应用中具有亚纳米分辨率的微米级研究，可用于研究蛋白质-DNA复合物，比如核小体，或具有DNA的蛋白质的LLPS，能够机械地理解分子信息如何在基因组水平上传播。
