دورية أكاديمية
Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods.
العنوان: | Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods. |
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المؤلفون: | Mai H; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California91125, United States., Zimmer MH; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California91125, United States., Miller TF 3rd; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California91125, United States. |
المصدر: | The journal of physical chemistry. B [J Phys Chem B] 2023 Jan 19; Vol. 127 (2), pp. 446-455. Date of Electronic Publication: 2023 Jan 06. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
اللغة: | English |
بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101157530 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5207 (Electronic) Linking ISSN: 15205207 NLM ISO Abbreviation: J Phys Chem B Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c1997- |
مواضيع طبية MeSH: | Ubiquitin-Protein Ligases*/chemistry , Ubiquitin-Protein Ligases*/metabolism , Proteins*/metabolism, Proteolysis ; Thermodynamics |
مستخلص: | Proteolysis targeting chimera (PROTAC) is a novel drug modality that facilitates the degradation of a target protein by inducing proximity with an E3 ligase. In this work, we present a new computational framework to model the cooperativity between PROTAC-E3 binding and PROTAC-target binding principally through protein-protein interactions (PPIs) induced by the PROTAC. Due to the scarcity and low resolution of experimental measurements, the physical and chemical drivers of these non-native PPIs remain to be elucidated. We develop a coarse-grained (CG) approach to model interactions in the target-PROTAC-E3 complexes, which enables converged thermodynamic estimations using alchemical free energy calculation methods despite an unconventional scale of perturbations. With minimal parametrization, we successfully capture fundamental principles of cooperativity, including the optimality of intermediate PROTAC linker lengths that originates from configurational entropy. We qualitatively characterize the dependency of cooperativity on PROTAC linker lengths and protein charges and shapes. Minimal inclusion of sequence- and conformation-specific features in our current force field, however, limits quantitative modeling to reproduce experimental measurements, but further development of the CG model may allow for efficient computational screening to optimize PROTAC cooperativity. |
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معلومات مُعتمدة: | R01 GM138845 United States GM NIGMS NIH HHS |
المشرفين على المادة: | EC 2.3.2.27 (Ubiquitin-Protein Ligases) 0 (Proteins) |
تواريخ الأحداث: | Date Created: 20230106 Date Completed: 20230120 Latest Revision: 20230926 |
رمز التحديث: | 20230926 |
مُعرف محوري في PubMed: | PMC9869335 |
DOI: | 10.1021/acs.jpcb.2c05795 |
PMID: | 36607139 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1520-5207 |
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DOI: | 10.1021/acs.jpcb.2c05795 |