标题： 分子粘合剂在三元复合物中稳定水介导的氢键 显示英文标题

标题： Molecular glues stabilize water-mediated hydrogen bonds in ternary complexes

摘要： 通过稳定弱的和瞬时的蛋白质-蛋白质相互作用（PPIs），分子粘合剂解决了靶向之前被认为不可成药的蛋白质的挑战。 雷帕霉素和WDB002是分子粘合剂，分别结合到FK506结合蛋白（FKBP12）并靶向FKBP12-雷帕霉素相关蛋白（FRAP）和中心体蛋白250（CEP250）。 在此，我们使用分子动力学模拟来深入了解分子粘合剂对蛋白质构象和PPIs的影响。 分子粘合剂调节了蛋白质的柔韧性，导致某些区域的柔韧性降低，并改变了蛋白质之间水介导的氢键的模式和稳定性。 我们的研究结果强调了在开发分子粘合剂的合理设计策略时，考虑水介导的氢键的重要性。 显示英文摘要

摘要： By stabilizing weak and transient protein-protein interactions (PPIs), molecular glues address the challenge of targeting proteins previously considered undruggable. Rapamycin and WDB002 are molecular glues that bind to FK506-binding protein (FKBP12) and target the FKBP12-rapamycin-associated protein (FRAP) and the centrosomal protein 250 (CEP250), respectively. Here, we used molecular dynamics simulations to gain insights into the effects of molecular glues on protein conformation and PPIs. The molecular glues modulated protein flexibility, leading to less flexibility in some regions, and changed the pattern and stability of water-mediated hydrogen bonds between the proteins. Our findings highlight the importance of considering water-mediated hydrogen bonds in developing strategies for the rational design of molecular glues.