Dissecting Dynamic and Hydration Contributions to Sequence-Dependent DNA Minor Groove Recognition.
Dissecting Dynamic and Hydration Contributions to Sequence-Dependent DNA Minor Groove Recognition.
复制标题
剖析动态和水合对序列依赖性 DNA 小沟识别的贡献。
DOI：
10.1016/j.bpj.2020.08.013
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发表时间：
2020
影响因子：
3.4
通讯作者：
Poon,GregoryMK
中科院分区：
文献类型：
--
作者：
Ha,VanLT;Erlitzki,Noa;Farahat,AbdelbassetA;Kumar,Arvind;Boykin,DavidW;Poon,GregoryMK
序列选择性是DNA结合配体的一个重要属性，并强调了在典型的序列环境中对结合的详细分子描述的必要性。我们研究了DB1976的结合和体积性质，DB1976是一种模型双(苯并咪唑)-硒二胺化合物，在急性髓系白血病、衰弱的纤维组织和肥胖相关的肝功能障碍中具有潜在的治疗潜力。为了采样同源DB1976靶点的范围，我们评估了三个跨越>；103倍的十二聚体双链结合亲和力。伴随而来的偏摩尔体积的变化很大程度上是不同的，但与结合亲和力不同步，这表明这些络合物中存在不同的相互作用模式。具体地说，最佳结合与水合水分的损失有关，而低亲和力结合释放更多的水合水分。显式原子分子动力学模拟表明，微小的沟槽结合以顺序依赖的方式扰乱了DNA末端和内部的构象动力学和水化作用。这些不同的局部动力学对水合作用的影响通过用盐进行区域特定的水合作用的询问得到了实验验证，该方法优先探测寡聚DNA带电的轴面而不是未带电的末端。因此，DB1976的次要凹槽识别产生了动态不同的结构域，这些结构域可以在高亲和力和低亲和力结合中对水化释放做出有利的贡献。由于DNA寡聚体内部位点的配体结合调节末端的动力学，结果表明沿着DNA靶的短期和长期动态效应都可以影响它们作为低分子量蛋白质结合竞争对手的有效性。
Sequence selectivity is a critical attribute of DNA-binding ligands and underlines the need for detailed molecular descriptions of binding in representative sequence contexts. We investigated the binding and volumetric properties of DB1976, a model bis(benzimidazole)-selenophene diamidine compound with emerging therapeutic potential in acute myeloid leukemia, debilitating fibroses, and obesity-related liver dysfunction. To sample the scope of cognate DB1976 target sites, we evaluated three dodecameric duplexes spanning >103-fold in binding affinity. The attendant changes in partial molar volumes varied substantially, but not in step with binding affinity, suggesting distinct modes of interactions in these complexes. Specifically, whereas optimal binding was associated with loss of hydration water, low-affinity binding released more hydration water. Explicit-atom molecular dynamics simulations showed that minor groove binding perturbed the conformational dynamics and hydration at the termini and interior of the DNA in a sequence-dependent manner. The impact of these distinct local dynamics on hydration was experimentally validated by domain-specific interrogation of hydration with salt, which probed the charged axial surfaces of oligomeric DNA preferentially over the uncharged termini. Minor groove recognition by DB1976, therefore, generates dynamically distinct domains that can make favorable contributions to hydration release in both high- and low-affinity binding. Because ligand binding at internal sites of DNA oligomers modulates dynamics at the termini, the results suggest both short- and long-range dynamic effects along the DNA target that can influence their effectiveness as low-MW competitors of protein binding.