Sequence-Specific Recognition of DNA by Proteins: Binding Motifs Discovered Using a Novel Statistical/Computational Analysis

Decades of intensive experimental studies of the recognition of DNA sequences by proteins have provided us with a view of a diverse and complicated world in which few to no features are shared between individual DNA-binding protein families. The originally conceived direct readout of DNA residue sequences by amino acid side chains offers very limited capacity for sequence recognition, while the effects of the dynamic properties of the interacting partners remain difficult to quantify and almost impossible to generalise. In this work we investigated the energetic characteristics of all DNA residue—amino acid side chain combinations in the conformations found at the interaction interface in a very large set of protein—DNA complexes by the means of empirical potential-based calculations. General specificity-defining criteria were derived and utilised to look beyond the binding motifs considered in previous studies. Linking energetic favourability to the observed geometrical preferences, our approach reveals several additional amino acid motifs which can distinguish between individual DNA bases. Our results remained valid in environments with various dielectric properties.

数十年来，针对蛋白质识别DNA序列开展的深入实验研究，为我们展现了一个纷繁复杂的研究图景：不同的DNA结合蛋白家族之间几乎不存在共通的识别特征。最初被提出的、由氨基酸侧链直接读取DNA残基序列的识别机制，其序列识别能力极为有限；而相互作用双方的动态特性所带来的影响，不仅难以量化，更几乎无法进行泛化推广。本研究针对超大规模蛋白质-DNA复合物集合中，位于相互作用界面的各类构象内的所有DNA残基-氨基酸侧链组合的能量特征，开展了基于经验势函数的计算分析。我们推导出通用的特异性判定准则，并借此拓展了此前研究的视野，不再局限于已报道的结合基序。通过将能量有利性与观测到的几何偏好性相结合，本研究方法还发现了若干可区分不同DNA碱基的新型氨基酸基序。本研究结果在不同介电特性的环境中均保持有效性。