Transcription factor proteins control the temporal and spatial expression of genes by binding specific regulatory elements, or motifs, in DNA. Mapping a transcription factor to its motif is an important step towards defining the structure of transcriptional regulatory networks and understanding their dynamics. The information to map a transcription factor to its DNA binding specificity is in principle contained in the protein sequence. Nevertheless, methods that map directly from protein sequence to target DNA sequence have been lacking, and generation of regulatory maps has required experimental data. Here we describe a purely computational method for predicting transcription factor binding. The method calculates the free energy of binding between a transcription factor and possible target DNA sequences using thermodynamic integration. Approximations of additivity (each DNA basepair contributes independently to the binding energy) and linear response (the DNA-protein and DNA-solvent couplings are linear in an effective reaction coordinate representing the basepair character at a specific position) make the computations feasible and can be verified by more detailed simulations. Results obtained for MAT-alpha2, a yeast homeodomain transcription factor, are in good agreement with known results. This method promises to provide a general, computationally feasible route from a genome sequence to a gene regulatory network.

中文翻译：

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解码转录调控相互作用。

转录因子蛋白通过结合DNA中的特定调控元件或基序来控制基因的时空表达。将转录因子映射到其基序是迈向定义转录调控网络结构并了解其动态的重要一步。蛋白质序列中原则上包含将转录因子映射为其DNA结合特异性的信息。然而，缺乏直接从蛋白质序列映射到靶DNA序列的方法，并且调节图谱的产生需要实验数据。在这里，我们描述了预测转录因子结合的纯计算方法。该方法使用热力学积分计算转录因子和可能的靶DNA序列之间结合的自由能。可加性的近似值（每个DNA碱基对独立地影响结合能）和线性响应（DNA-蛋白质和DNA-溶剂偶合在表示特定位置碱基对特征的有效反应坐标中是线性的）使计算可行，并且可以经过更详细的模拟验证。酵母同源域转录因子MAT-alpha2获得的结果与已知结果高度吻合。该方法有望提供从基因组序列到基因调控网络的通用，在计算上可行的途径。