In silico modeling was applied to study the efficiency of two ligands, namely, UCB-J and UCB-F, to bind to isoforms of the synaptic vesicle glycoprotein 2 (SV2) that are involved in the regulation of synaptic function in the nerve terminals, with the ultimate goal to understand the selectivity of the interaction between UCB-J and UCB-F to different isoforms of SV2. Docking and large-scale molecular dynamics simulations were carried out to unravel various binding patterns, types of interactions, and binding free energies, covering hydrogen bonding and nonspecific hydrophobic interactions, water bridge, π–π, and cation−π interactions. The overall preference for bonding types of UCB-J and UCB-F with particular residues in the protein pockets can be disclosed in detail. A unique interaction fingerprint, namely, hydrogen bonding with additional cation−π interaction with the pyridine moiety of UCB-J, could be established as an explanation for its high selectivity over the SV2 isoform A (SV2A). Other molecular details, primarily referring to the presence of π–π interactions and hydrogen bonding, could also be analyzed as sources of selectivity of the UCB-F tracer for the three isoforms. The simulations provide atomic details to support future development of new selective tracers targeting synaptic vesicle glycoproteins and their associated diseases.

中文翻译：

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探索两种配体 UCB-J 和 UCB-F 与突触小泡糖蛋白 2 异构体之间的相互作用


应用计算机模型研究两种配体（即 UCB-J 和 UCB-F）与参与神经末梢突触功能调节的突触小泡糖蛋白 2 (SV2) 亚型结合的效率，最终目标是了解 UCB-J 和 UCB-F 之间的相互作用对 SV2 不同亚型的选择性。进行了对接和大规模分子动力学模拟，以揭示各种结合模式、相互作用类型和结合自由能，涵盖氢键和非特异性疏水相互作用、水桥、π-π和阳离子-π相互作用。可以详细公开 UCB-J 和 UCB-F 与蛋白质袋中特定残基的键合类型的总体偏好。一个独特的相互作用指纹，即氢键与 UCB-J 吡啶部分的额外阳离子-π 相互作用，可以解释其对 SV2 同工型 A (SV2A) 的高选择性。其他分子细节，主要是指 π-π 相互作用和氢键的存在，也可以作为 UCB-F 示踪剂对三种亚型的选择性来源进行分析。这些模拟提供了原子细节，以支持未来开发针对突触囊泡糖蛋白及其相关疾病的新型选择性示踪剂。