Rational designs of pharmaceutical compounds targeting specific RNAs require a comprehensive understanding of molecular recognition mechanisms. Knowledge of binding affinity and specificity can be gained via computational modeling and simulation techniques. In this work, an integrated computational strategy combining QM calculation, molecular docking, conventional and adaptive steered MD simulations, and the var-MM/GBSA approach was proposed to probe the binding behaviors of daunomycin (DAU) and phenylalanine transfer RNA (tRNA^Phe) at a micro-scale level. Gathering experimental information enables us to eliminate improper predictions for the binding of DAU and tRNA^Phe, and the calculations of PMF and ΔG_binding lead to the identification of the binding structure of the complex. Further, structural and energetic analysis of the DAU:tRNA^Phe complex revealed that daunomycinone of DAU contributes the intermolecular VDW energies to nucleotides G₁₅, C₄₈ and U₅₉ on tRNA^Phe, responsible for the binding specificity; meanwhile daunosamine contributes the intermolecular ELE + EGB energies to U₅₀, responsible for the binding affinity.

中文翻译：

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道诺霉素与苯丙氨酸转移 RNA 结合的计算机研究：用于基于结构的药物设计的探针分子识别

针对特定 RNA 的药物化合物的合理设计需要对分子识别机制有全面的了解。结合亲和力和特异性的知识可以通过计算建模和模拟技术获得。在这项工作中，提出了一种结合 QM 计算、分子对接、常规和自适应转向 MD 模拟以及 var-MM/GBSA 方法的综合计算策略来探测道诺霉素 (DAU) 和苯丙氨酸转移 RNA (tRNA Phe) 的^结合行为在微观层面。^{收集实验信息使我们能够消除对 DAU 和 tRNA Phe}结合的不正确预测，以及 PMF 和 Δ G_结合的计算导致识别复合物的结合结构。此外，DAU:tRNA ^Phe复合物的结构和能量分析表明，DAU 的道诺霉素为tRNA ^{Phe上的核苷酸 G} ₁₅、C ₄₈和 U ₅₉贡献分子间 VDW 能量，负责结合特异性；同时， daunosamine 将分子间 ELE + EGB 能量贡献给 U ₅₀，负责结合亲和力。