Complex Carbohydrate Research Center , University of Georgia , Athens , Georgia 30602 , United States.
Biology and Soft Matter Division , Oak Ridge National Laboratory , Oak Ridge , Tennessee 37831 , United States.
J Chem Inf Model. 2018 Sep 24;58(9):1889-1901. doi: 10.1021/acs.jcim.8b00120. Epub 2018 Aug 22.
Protein-carbohydrate interactions are significant in a wide range of biological processes, disruption of which has been implicated in many different diseases. The capability of glycan-binding proteins (GBPs) to specifically bind to the corresponding glycans allows GBPs to be utilized in glycan biomarker detection or conversely to serve as targets for therapeutic intervention. However, understanding the structural origins of GBP specificity has proven to be challenging due to their typically low binding affinities (mM) and their potential to display broad or complex specificities. Here we perform molecular dynamics (MD) simulations and post-MD energy analyses with the Poisson-Boltzmann and generalized Born solvent models (MM-PB/GBSA) of the Erythrina cristagalli lectin (ECL) with its known ligands, and with new cocrystal structures reported herein. While each MM-PB/GBSA parametrization resulted in different estimates of the desolvation free energy, general trends emerged that permit us to define GBP binding preferences in terms of ligand substructure specificity. Additionally, we have further decomposed the theoretical interaction energies into contributions made between chemically relevant functional groups. Based on these contributions, the functional groups in each ligand can be assembled into a pharmacophore comprised of groups that are either critical for binding, or enhance binding, or are noninteracting. It is revealed that the pharmacophore for ECL consists of the galactopyranose (Gal) ring atoms along with C6 and the O3 and O4 hydroxyl groups. This approach provides a convenient method for identifying and quantifying the glycan pharmacophore and provides a novel method for interpreting glycan specificity that is independent of residue-level glycan nomenclature. A pharmacophore approach to defining specificity is readily transferable to molecular design software and, therefore, may be particularly useful in designing therapeutics (glycomimetics) that target GBPs.
蛋白质-碳水化合物相互作用在广泛的生物学过程中具有重要意义，其破坏与许多不同疾病有关。糖结合蛋白（GBP）能够特异性结合相应糖链的能力使其能够用于糖生物标志物的检测，或者反过来作为治疗干预的靶点。然而，由于其通常较低的结合亲和力（mM）及其潜在的广泛或复杂特异性，理解 GBP 特异性的结构起源一直具有挑战性。在这里，我们使用泊松-玻尔兹曼和广义 Born 溶剂模型（MM-PB/GBSA）对已知配体及其在此处报道的新共晶结构进行分子动力学（MD）模拟和 MD 后能量分析。虽然每个 MM-PB/GBSA 参数化都导致了不同的去溶剂自由能估计，但出现了一些总体趋势，使我们能够根据配体亚结构特异性来定义 GBP 结合偏好。此外，我们还进一步将理论相互作用能分解为化学相关功能基团之间的贡献。基于这些贡献，可以将每个配体中的功能基团组装成一个药效团，该药效团由对结合至关重要的基团、增强结合的基团或非相互作用的基团组成。结果表明，ECL 的药效团由半乳糖吡喃糖（Gal）环原子以及 C6 和 O3 和 O4 羟基组成。这种方法提供了一种方便的方法来识别和量化糖的药效团，并提供了一种独立于残基水平糖命名法的解释糖特异性的新方法。定义特异性的药效团方法很容易转移到分子设计软件中，因此在设计针对 GBP 的治疗药物（糖模拟物）时可能特别有用。
