Physicochemical models of protein-DNA binding with standard and modified base pairs.
Physicochemical models of protein-DNA binding with standard and modified base pairs.
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蛋白质-DNA 与标准碱基对和修饰碱基对结合的物理化学模型。
DOI：
10.1073/pnas.2205796120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Watson-Crick序列模型能够简化DNA的表示，其中四个字母A、C、G和T描述所有可能的核苷酸对的化学同一性和方向。在这个粗粒度模型中，每个字母描述了一个超过60个原子的集合。然而，核苷酸对的原子组成可以通过化学修饰、不同的碱基配对几何构型或错配来改变。由于只有几个原子有助于结合特异性，我们认为，与序列模型相比，直接编码蛋白质-DNA接触的基于化学的模型可能更有力地捕捉DNA的化学变异。我们介绍了直接和精确地表示物理化学读数的模型，重要的是，这不限于标准的沃森-克里克碱基对。DNA结合蛋白在各种细胞过程中发挥着重要作用，但蛋白质识别基因组靶点的机制仍不完全清楚。暴露在DNA凹槽中的碱基对(BP)边缘的官能团代表物理化学特征。由于这些特征使蛋白质能够在蛋白质残基和BP之间形成特定的接触，他们的研究可以提供对蛋白质-DNA结合的机械性见解。现有的实验方法，如X射线结晶学，可以揭示这种基于蛋白质与其DNA靶点之间的物理化学相互作用的机制。然而，结构生物学方法的低吞吐量限制了对许多基因组位置选择的机械性见解。高通量结合分析通过确定蛋白质与大量DNA序列的相对结合亲和力来预测潜在的靶点。目前许多可用的计算方法都是基于标准的Watson-Crick BP序列。他们假设总结合亲和力的贡献对于每个碱基对是独立的，或者替代地包括二核苷酸或短k-MERS。这些方法不能直接扩展到物理化学接触，也不适用于DNA修饰或非Watson-Crick BP。这些变异包括DNA甲基化，以及合成或错配的BP。所提出的方法DeepRec可以预测相对结合亲和力作为物理化学特征以及DNA甲基化或其他化学修饰对结合的影响的函数。相比之下，基于序列的建模方法是一种粗粒度的描述，无法实现这种洞察。我们基于化学的建模框架提供了一条在机械水平上理解基因组功能的途径。
The Watson–Crick sequence model enables a simplified representation of DNA, wherein four letters, A, C, G, and T, describe the chemical identities and orientations of all possible nucleotide pairs. In this coarse-grained model, each letter describes an assembly of over 60 atoms. However, the atomic composition of a nucleotide pair can be altered by chemical modifications, different base-pairing geometries, or mismatches. As only a few atoms contribute to binding specificity, we propose that compared to a sequence model, a chemistry-based model that directly encodes protein–DNA contacts may more robustly capture the chemical variations of DNA. We introduce models that directly and precisely represent physicochemical readout, which is, importantly, not restricted to standard Watson–Crick base pairs. DNA-binding proteins play important roles in various cellular processes, but the mechanisms by which proteins recognize genomic target sites remain incompletely understood. Functional groups at the edges of the base pairs (bp) exposed in the DNA grooves represent physicochemical signatures. As these signatures enable proteins to form specific contacts between protein residues and bp, their study can provide mechanistic insights into protein–DNA binding. Existing experimental methods, such as X-ray crystallography, can reveal such mechanisms based on physicochemical interactions between proteins and their DNA target sites. However, the low throughput of structural biology methods limits mechanistic insights for selection of many genomic sites. High-throughput binding assays enable prediction of potential target sites by determining relative binding affinities of a protein to massive numbers of DNA sequences. Many currently available computational methods are based on the sequence of standard Watson–Crick bp. They assume that the contribution of overall binding affinity is independent for each base pair, or alternatively include dinucleotides or short k-mers. These methods cannot directly expand to physicochemical contacts, and they are not suitable to apply to DNA modifications or non-Watson–Crick bp. These variations include DNA methylation, and synthetic or mismatched bp. The proposed method, DeepRec, can predict relative binding affinities as function of physicochemical signatures and the effect of DNA methylation or other chemical modifications on binding. Sequence-based modeling methods are in comparison a coarse-grain description and cannot achieve such insights. Our chemistry-based modeling framework provides a path towards understanding genome function at a mechanistic level.
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影响因子：
46.9
作者：
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通讯作者：
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