The recognition of carbohydrates by lectins play key roles in diverse cellular processes such as cellular adhesion, proliferation and apoptosis which makes it a promising therapeutic target against cancers. One of the most functionally active lectins, galectin-3 is distinctively known for its specific binding affinity towards β-galactoside. Despite the prevalence of high-resolution crystallographic structures, the mechanistic basis and the molecular determinants of the sugar recognition process by galectin-3 are currently elusive. Here we address this question by capturing the complete dynamical binding process of human galectin-3 with its native ligand N-acetyllactosamine (LacNAc) and one of its synthetic derivatives by unbiased Molecular Dynamics simulation. In our simulations, both the natural ligand LacNAc and its synthetic derivative, initially solvated in water, diffuse around the protein and eventually recognise the designated binding site at the S-side of galectin-3, in crystallographic precision and identifies key metastable intermediate ligand-states around the galectin on their course to eventual binding. The simulations highlight that the origin of the experimentally observed multi-fold efficacy of synthetically designed ligand-derivative over its native natural ligand LacNAc lies in the derivative’s relatively longer residence time in the bound pocket. A kinetic analysis demonstrates that the LacNAc-derivative would be more resilient compared to the parent ligand against unbinding from the protein binding site. In particular, the analysis identifies that interactions of the binding pocket residues Trp181, Arg144 and Arg162 with the tetrafuorophenyl ring of the derivative as the key determinant for the synthetic ligand to latch into the pocket.

中文翻译：

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半乳糖凝集素中配体驻留的分子决定因素

凝集素对碳水化合物的识别在细胞粘附、增殖和凋亡等多种细胞过程中起着关键作用，这使其成为有希望的抗癌治疗靶点。作为功​​能最活跃的凝集素之一，半乳糖凝集素 3 以其对β 的特异性结合亲和力而著称-半乳糖苷。尽管高分辨率晶体结构普遍存在，但目前尚不清楚 galectin-3 糖识别过程的机制基础和分子决定因素。在这里，我们通过无偏分子动力学模拟捕获人类半乳糖凝集素 3 与其天然配体 N-乙酰乳糖胺 (LacNAc) 及其合成衍生物之一的完整动态结合过程来解决这个问题。在我们的模拟中，天然配体 LacNAc 及其合成衍生物，最初溶解在水中，在蛋白质周围扩散，最终以晶体学精度识别半乳糖凝集素 3 S 侧的指定结合位点，并识别关键的亚稳态中间配体 -围绕半乳糖凝集素进行最终结合的状态。模拟强调，实验观察到的合成设计的配体衍生物对其天然天然配体 LacNAc 的多重功效的起源在于衍生物在结合口袋中相对较长的停留时间。动力学分析表明，与亲本配体相比，LacNAc 衍生物更能抵抗从蛋白质结合位点解离。特别是，该分析确定结合口袋残基 Trp181、Arg144 和 Arg162 与衍生物的四氟苯环的相互作用是合成配体锁定到口袋中的关键决定因素。动力学分析表明，与亲本配体相比，LacNAc 衍生物更能抵抗从蛋白质结合位点解离。特别是，该分析确定结合口袋残基 Trp181、Arg144 和 Arg162 与衍生物的四氟苯环的相互作用是合成配体锁定到口袋中的关键决定因素。动力学分析表明，与亲本配体相比，LacNAc 衍生物更能抵抗从蛋白质结合位点的解离。特别是，该分析确定结合口袋残基 Trp181、Arg144 和 Arg162 与衍生物的四氟苯环的相互作用是合成配体锁定到口袋中的关键决定因素。