Ligand binding remodels protein side-chain conformational heterogeneity
While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-03-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/74114 |
| _version_ | 1811203613216735232 |
|---|---|
| author | Stephanie A Wankowicz Saulo H de Oliveira Daniel W Hogan Henry van den Bedem James S Fraser |
| author_facet | Stephanie A Wankowicz Saulo H de Oliveira Daniel W Hogan Henry van den Bedem James S Fraser |
| author_sort | Stephanie A Wankowicz |
| collection | DOAJ |
| description | While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, through multiconformer modeling of time- and space-averaged electron density, we measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity of side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent-exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decreases and relative hydrophobicity increases. Across a series of 13 inhibitor-bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from nuclear magnetic resonance studies suggesting that residual side-chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding. |
| first_indexed | 2024-04-12T02:58:18Z |
| format | Article |
| id | doaj.art-42e8ec0d84fa4d86ba8fa90a81eae627 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:58:18Z |
| publishDate | 2022-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-42e8ec0d84fa4d86ba8fa90a81eae6272022-12-22T03:50:44ZengeLife Sciences Publications LtdeLife2050-084X2022-03-011110.7554/eLife.74114Ligand binding remodels protein side-chain conformational heterogeneityStephanie A Wankowicz0https://orcid.org/0000-0002-4225-7459Saulo H de Oliveira1Daniel W Hogan2Henry van den Bedem3James S Fraser4https://orcid.org/0000-0002-5080-2859Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States; Biophysics Graduate Program, University of California San Francisco, San Francisco, United StatesAtomwise Inc., San Francisco, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States; Atomwise Inc., San Francisco, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United StatesWhile protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, through multiconformer modeling of time- and space-averaged electron density, we measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity of side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent-exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decreases and relative hydrophobicity increases. Across a series of 13 inhibitor-bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from nuclear magnetic resonance studies suggesting that residual side-chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding.https://elifesciences.org/articles/74114ligand bindingconformational entropyconformational ensembles |
| spellingShingle | Stephanie A Wankowicz Saulo H de Oliveira Daniel W Hogan Henry van den Bedem James S Fraser Ligand binding remodels protein side-chain conformational heterogeneity eLife ligand binding conformational entropy conformational ensembles |
| title | Ligand binding remodels protein side-chain conformational heterogeneity |
| title_full | Ligand binding remodels protein side-chain conformational heterogeneity |
| title_fullStr | Ligand binding remodels protein side-chain conformational heterogeneity |
| title_full_unstemmed | Ligand binding remodels protein side-chain conformational heterogeneity |
| title_short | Ligand binding remodels protein side-chain conformational heterogeneity |
| title_sort | ligand binding remodels protein side chain conformational heterogeneity |
| topic | ligand binding conformational entropy conformational ensembles |
| url | https://elifesciences.org/articles/74114 |
| work_keys_str_mv | AT stephanieawankowicz ligandbindingremodelsproteinsidechainconformationalheterogeneity AT saulohdeoliveira ligandbindingremodelsproteinsidechainconformationalheterogeneity AT danielwhogan ligandbindingremodelsproteinsidechainconformationalheterogeneity AT henryvandenbedem ligandbindingremodelsproteinsidechainconformationalheterogeneity AT jamessfraser ligandbindingremodelsproteinsidechainconformationalheterogeneity |