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| Autori principali: | , , , , |
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| Natura: | Preprint |
| Pubblicazione: |
2025
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| Soggetti: | |
| Accesso online: | https://arxiv.org/abs/2510.26806 |
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| _version_ | 1866911241090367488 |
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| author | Mathur, Apoorva Canela, Mariona Alegre von Graevenitz, Max Gerstner, Chiara Nunes-Alves, Ariane |
| author_facet | Mathur, Apoorva Canela, Mariona Alegre von Graevenitz, Max Gerstner, Chiara Nunes-Alves, Ariane |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2510_26806 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Molecular glues stabilize water-mediated hydrogen bonds in ternary complexes Mathur, Apoorva Canela, Mariona Alegre von Graevenitz, Max Gerstner, Chiara Nunes-Alves, Ariane Biomolecules 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. |
| title | Molecular glues stabilize water-mediated hydrogen bonds in ternary complexes |
| topic | Biomolecules |
| url | https://arxiv.org/abs/2510.26806 |