Anchored design of protein-protein interfaces.
Few existing protein-protein interface design methods allow for extensive backbone rearrangements during the design process. There is also a dichotomy between redesign methods, which take advantage of the native interface, and de novo methods, which produce novel binders.Here, we propose a new metho...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3117852?pdf=render |
| _version_ | 1818083152305848320 |
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| author | Steven M Lewis Brian A Kuhlman |
| author_facet | Steven M Lewis Brian A Kuhlman |
| author_sort | Steven M Lewis |
| collection | DOAJ |
| description | Few existing protein-protein interface design methods allow for extensive backbone rearrangements during the design process. There is also a dichotomy between redesign methods, which take advantage of the native interface, and de novo methods, which produce novel binders.Here, we propose a new method for designing novel protein reagents that combines advantages of redesign and de novo methods and allows for extensive backbone motion. This method requires a bound structure of a target and one of its natural binding partners. A key interaction in this interface, the anchor, is computationally grafted out of the partner and into a surface loop on the design scaffold. The design scaffold's surface is then redesigned with backbone flexibility to create a new binding partner for the target. Careful choice of a scaffold will bring experimentally desirable characteristics into the new complex. The use of an anchor both expedites the design process and ensures that binding proceeds against a known location on the target. The use of surface loops on the scaffold allows for flexible-backbone redesign to properly search conformational space.This protocol was implemented within the Rosetta3 software suite. To demonstrate and evaluate this protocol, we have developed a benchmarking set of structures from the PDB with loop-mediated interfaces. This protocol can recover the correct loop-mediated interface in 15 out of 16 tested structures, using only a single residue as an anchor. |
| first_indexed | 2024-12-10T19:33:27Z |
| format | Article |
| id | doaj.art-1941e35254164cee87913447e9ef7dae |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T19:33:27Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1941e35254164cee87913447e9ef7dae2022-12-22T01:36:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0166e2087210.1371/journal.pone.0020872Anchored design of protein-protein interfaces.Steven M LewisBrian A KuhlmanFew existing protein-protein interface design methods allow for extensive backbone rearrangements during the design process. There is also a dichotomy between redesign methods, which take advantage of the native interface, and de novo methods, which produce novel binders.Here, we propose a new method for designing novel protein reagents that combines advantages of redesign and de novo methods and allows for extensive backbone motion. This method requires a bound structure of a target and one of its natural binding partners. A key interaction in this interface, the anchor, is computationally grafted out of the partner and into a surface loop on the design scaffold. The design scaffold's surface is then redesigned with backbone flexibility to create a new binding partner for the target. Careful choice of a scaffold will bring experimentally desirable characteristics into the new complex. The use of an anchor both expedites the design process and ensures that binding proceeds against a known location on the target. The use of surface loops on the scaffold allows for flexible-backbone redesign to properly search conformational space.This protocol was implemented within the Rosetta3 software suite. To demonstrate and evaluate this protocol, we have developed a benchmarking set of structures from the PDB with loop-mediated interfaces. This protocol can recover the correct loop-mediated interface in 15 out of 16 tested structures, using only a single residue as an anchor.http://europepmc.org/articles/PMC3117852?pdf=render |
| spellingShingle | Steven M Lewis Brian A Kuhlman Anchored design of protein-protein interfaces. PLoS ONE |
| title | Anchored design of protein-protein interfaces. |
| title_full | Anchored design of protein-protein interfaces. |
| title_fullStr | Anchored design of protein-protein interfaces. |
| title_full_unstemmed | Anchored design of protein-protein interfaces. |
| title_short | Anchored design of protein-protein interfaces. |
| title_sort | anchored design of protein protein interfaces |
| url | http://europepmc.org/articles/PMC3117852?pdf=render |
| work_keys_str_mv | AT stevenmlewis anchoreddesignofproteinproteininterfaces AT brianakuhlman anchoreddesignofproteinproteininterfaces |