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Rational Design and In Vitro Evaluation of Novel Peptides Binding to Neuroligin-1 for Synaptic Targeting.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-01-07 , DOI: 10.1021/acs.jcim.9b01003 Pilar Vásquez 1 , Felipe Vidal 1 , Josefa Torres 1 , Verónica A Jiménez 2 , Leonardo Guzmán 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-01-07 , DOI: 10.1021/acs.jcim.9b01003 Pilar Vásquez 1 , Felipe Vidal 1 , Josefa Torres 1 , Verónica A Jiménez 2 , Leonardo Guzmán 1
Affiliation
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Neuroligin-1 (NL1) is a postsynaptic cell adhesion protein that plays a crucial role in synapsis and signaling between neurons. Due to its clustered distribution in synaptic clefts, NL1 appears as a novel potential site for synaptic targeting purposes. In this work, in silico protein topography analysis was employed to identify two prospective binding sites on the NL1 dimer surface in the 2:2 synaptic adhesion complex with β-neurexin (PDB code 3B3Q ). Receptor-based rational design, cell-penetrating capability prediction, molecular docking, molecular dynamics simulations, and binding free energy calculations were used to identify five heptapeptides candidates with favorable predicted profiles as non cell-penetrating NL1-binding agents. Preliminary in vitro colocalization assays with NL1-transfected HEK 293 cells confirmed that peptides remain in the extracellular space without inducing detectable changes in cell morphology. The highest NL1-colocatization capability was attained by the peptide ADEAIVA, which appears as a promising candidate for the future development of specific NL1-targeting systems as part of synapse-directed therapies against central nervous system diseases.
中文翻译：
合理设计和体外评估新型肽结合Neuroligin-1的突触靶向。
Neuroligin-1（NL1）是突触后细胞粘附蛋白，在神经元之间的突触和信号传导中起关键作用。由于其在突触裂隙中的成簇分布，NL1似乎是用于突触靶向的新型潜在位点。在这项工作中，采用计算机蛋白质拓扑分析方法来鉴定与β-神经毒素（PDB代码3B3Q）形成的2：2突触粘附复合物中NL1二聚体表面上的两个预期结合位点。基于受体的合理设计，细胞穿透能力预测，分子对接，分子动力学模拟和结合自由能计算被用来识别具有良好预测特性的五种七肽候选物作为非细胞穿透性NL1结合剂。NL1转染的HEK 293细胞的初步体外共定位测定证实，肽保留在细胞外空间中，而不会引起细胞形态的可检测变化。肽ADEAIVA获得了最高的NL1定位能力，该肽有望成为未来针对特定NL1靶向系统的未来开发的有前途的候选物，作为针对中枢神经系统疾病的突触定向疗法的一部分。
更新日期：2020-01-07
中文翻译：
合理设计和体外评估新型肽结合Neuroligin-1的突触靶向。
Neuroligin-1（NL1）是突触后细胞粘附蛋白，在神经元之间的突触和信号传导中起关键作用。由于其在突触裂隙中的成簇分布，NL1似乎是用于突触靶向的新型潜在位点。在这项工作中，采用计算机蛋白质拓扑分析方法来鉴定与β-神经毒素（PDB代码3B3Q）形成的2：2突触粘附复合物中NL1二聚体表面上的两个预期结合位点。基于受体的合理设计，细胞穿透能力预测，分子对接，分子动力学模拟和结合自由能计算被用来识别具有良好预测特性的五种七肽候选物作为非细胞穿透性NL1结合剂。NL1转染的HEK 293细胞的初步体外共定位测定证实，肽保留在细胞外空间中，而不会引起细胞形态的可检测变化。肽ADEAIVA获得了最高的NL1定位能力，该肽有望成为未来针对特定NL1靶向系统的未来开发的有前途的候选物，作为针对中枢神经系统疾病的突触定向疗法的一部分。
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