The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions
Our interpretation of ligand–protein interactions is often informed by high-resolution structures, which represent the cornerstone of structure-based drug design. However, visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum Mecha...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2015
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| _version_ | 1797100442270826496 |
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| author | Heifetz, A Chudyk, E Gleave, L Aldeghi, M Cherezov, V Fedorov, D Biggin, P Bodkin, M |
| author_facet | Heifetz, A Chudyk, E Gleave, L Aldeghi, M Cherezov, V Fedorov, D Biggin, P Bodkin, M |
| author_sort | Heifetz, A |
| collection | OXFORD |
| description | Our interpretation of ligand–protein interactions is often informed by high-resolution structures, which represent the cornerstone of structure-based drug design. However, visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum Mechanics approaches are often too computationally expensive, but one method, Fragment Molecular Orbital (FMO), offers an excellent compromise and has the potential to reveal key interactions that would otherwise be hard to detect. To illustrate this, we have applied the FMO method to 18 Class A GPCR–ligand crystal structures, representing different branches of the GPCR genome. Our work reveals key interactions that are often omitted from structure-based descriptions, including hydrophobic interactions, nonclassical hydrogen bonds, and the involvement of backbone atoms. This approach provides a more comprehensive picture of receptor–ligand interactions than is currently used and should prove useful for evaluation of the chemical nature of ligand binding and to support structure-based drug design. |
| first_indexed | 2024-03-07T05:37:34Z |
| format | Journal article |
| id | oxford-uuid:e46e7d6d-0eda-4f95-8ab7-393e83d6f2f7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:37:34Z |
| publishDate | 2015 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:e46e7d6d-0eda-4f95-8ab7-393e83d6f2f72022-03-27T10:16:39ZThe fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactionsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e46e7d6d-0eda-4f95-8ab7-393e83d6f2f7EnglishSymplectic Elements at OxfordAmerican Chemical Society2015Heifetz, AChudyk, EGleave, LAldeghi, MCherezov, VFedorov, DBiggin, PBodkin, MOur interpretation of ligand–protein interactions is often informed by high-resolution structures, which represent the cornerstone of structure-based drug design. However, visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum Mechanics approaches are often too computationally expensive, but one method, Fragment Molecular Orbital (FMO), offers an excellent compromise and has the potential to reveal key interactions that would otherwise be hard to detect. To illustrate this, we have applied the FMO method to 18 Class A GPCR–ligand crystal structures, representing different branches of the GPCR genome. Our work reveals key interactions that are often omitted from structure-based descriptions, including hydrophobic interactions, nonclassical hydrogen bonds, and the involvement of backbone atoms. This approach provides a more comprehensive picture of receptor–ligand interactions than is currently used and should prove useful for evaluation of the chemical nature of ligand binding and to support structure-based drug design. |
| spellingShingle | Heifetz, A Chudyk, E Gleave, L Aldeghi, M Cherezov, V Fedorov, D Biggin, P Bodkin, M The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions |
| title | The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions |
| title_full | The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions |
| title_fullStr | The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions |
| title_full_unstemmed | The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions |
| title_short | The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions |
| title_sort | fragment molecular orbital method reveals new insight into the chemical nature of gpcr ligand interactions |
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