2026-10-12T00:26:19Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33995012 2026-09-25T12:19:23Z category_1 category_4 category_7 category_12 category_14 category_15 category_21 category_873 category_46 category_734 category_64 portal_63 item_type_3 month_year_09_2026

In Silico Evaluation of the Effects of Temperature on the Affinity of the SV2C Ligand UCB-1A to SV2 Paralogs Rongfeng Zou (4338469) Sangram Nag (2153485) Vasco Sousa (25109867) Anton Morén (25109870) Miklós Tóth (8939063) Yasir Khani (25109873) Elena Pedergnana (25109876) Anne Valade (2160319) Celine Vermeiren (25109879) Philippe Motte (25109882) Joël Mercier (3127386) Xiaoqun Zhang (849862) Per Svenningsson (442585) Christer Halldin (314522) Andrea Varrone (436069) Hans Ågren (472815) Biophysics Biochemistry Medicine Cell Biology Molecular Biology Neuroscience Biotechnology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Cancer many trajectories exceeding 37 ° c ligand rmsd values unique stabilizing feature structural analysis showed reinforces pocket stability persistent hydrogen bond binding studies revealed 4 ° c greater temperature sensitivity sv2a decreased significantly sv2c ligand displaying sv2 ligand evaluation md simulations reproduced sv2c ligand ucb structural feature hydrogen bond ligand selective ligand recognition silico evaluation whereas binding uncover isoform specific mechanisms results highlight potential candidate parkinson ’ paralogs stabilized neurotransmitter release molecular dynamics mechanistic explanation less exposed investigated whether induced destabilization findings provide combining experiments Synaptic vesicle glycoproteins 2 (SV2) are integral membrane proteins essential for neurotransmitter release and are implicated in neurological disorders including epilepsy and Parkinson’s disease. In the attempt to develop a ligand selective for SV2C, and i in collaboration with UCB Biopharma, UCB-F was identified as a potential candidate. However, the affinity of UCB-F to SV2C was found to be temperature dependent, decreasing by about 10-fold from 4 to 37 °C. UCB-1A was subsequently identified as SV2C ligand displaying in vitro a 100-fold selectivity for SV2C compared with SV2A. In this study, we investigated whether the binding of UCB-1A to SV2A and SV2C was affected by the temperature. A combination of experimental binding assay data and molecular dynamics (MD) simulations were used. The binding studies revealed that UCB-1A affinity for SV2A decreased significantly at 37 °C compared with 4 °C, whereas binding to SV2C remained largely unchanged. MD simulations reproduced these observations, namely that ligand RMSD values at 37 °C showed that UCB-1A binding fluctuated markedly in the SV2A complex, with many trajectories exceeding the 3.0 Å stability cutoff, whereas UCB-1A remained relatively well-anchored in SV2C under the same conditions. Structural analysis showed that, while UCB-1A adopts a conserved binding pose across all paralogs stabilized by π–π stacking and a hydrogen bond with Asp, SV2C possesses a unique stabilizing feature. In SV2C, Tyr298 is less exposed to the solvent and engages in a persistent hydrogen bond with Asparagine, a structural feature that reinforces pocket stability and limits temperature-induced destabilization. This interaction is absent in SV2A, consistent with its greater temperature sensitivity. Together, these findings provide a mechanistic explanation for the experimentally observed temperature independence of UCB-1A binding to SV2C. More broadly, the results highlight the importance of incorporating physiologically relevant temperatures into SV2 ligand evaluation and demonstrate how combining experiments with simulations can uncover isoform-specific mechanisms of ligand recognition and stability. 2026-09-25T00:00:00Z Dataset Dataset 10.1021/acschemneuro.6c00482.s001 https://figshare.com/articles/dataset/In_Silico_Evaluation_of_the_Effects_of_Temperature_on_the_Affinity_of_the_SV2C_Ligand_UCB-1A_to_SV2_Paralogs/33995012 CC BY-NC 4.0