Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations
We develop integrated co-evolution and dynamic coupling (ICDC) approach to identify, mutate, and assess distal sites to modulate function. We validate the approach first by analyzing the existing mutational fitness data of TEM-1 β-lactamase and show that allosteric positions co-evolved and dynamical...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-12-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67474 |
| _version_ | 1811212795178385408 |
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| author | I Can Kazan Prerna Sharma Mohammad Imtiazur Rahman Andrey Bobkov Raimund Fromme Giovanna Ghirlanda S Banu Ozkan |
| author_facet | I Can Kazan Prerna Sharma Mohammad Imtiazur Rahman Andrey Bobkov Raimund Fromme Giovanna Ghirlanda S Banu Ozkan |
| author_sort | I Can Kazan |
| collection | DOAJ |
| description | We develop integrated co-evolution and dynamic coupling (ICDC) approach to identify, mutate, and assess distal sites to modulate function. We validate the approach first by analyzing the existing mutational fitness data of TEM-1 β-lactamase and show that allosteric positions co-evolved and dynamically coupled with the active site significantly modulate function. We further apply ICDC approach to identify positions and their mutations that can modulate binding affinity in a lectin, cyanovirin-N (CV-N), that selectively binds to dimannose, and predict binding energies of its variants through Adaptive BP-Dock. Computational and experimental analyses reveal that binding enhancing mutants identified by ICDC impact the dynamics of the binding pocket, and show that rigidification of the binding residues compensates for the entropic cost of binding. This work suggests a mechanism by which distal mutations modulate function through dynamic allostery and provides a blueprint to identify candidates for mutagenesis in order to optimize protein function. |
| first_indexed | 2024-04-12T05:35:14Z |
| format | Article |
| id | doaj.art-10f06b29d61c4ec18c13b76110549cdb |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T05:35:14Z |
| publishDate | 2022-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-10f06b29d61c4ec18c13b76110549cdb2022-12-22T03:45:53ZengeLife Sciences Publications LtdeLife2050-084X2022-12-011110.7554/eLife.67474Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutationsI Can Kazan0https://orcid.org/0000-0003-2593-4179Prerna Sharma1Mohammad Imtiazur Rahman2Andrey Bobkov3Raimund Fromme4Giovanna Ghirlanda5https://orcid.org/0000-0001-5470-1484S Banu Ozkan6https://orcid.org/0000-0002-9351-3758Center for Biological Physics and Department of Physics, Arizona State University, Tempe, United States; School of Molecular Sciences, Arizona State University, Tempe, United StatesSchool of Molecular Sciences, Arizona State University, Tempe, United StatesSchool of Molecular Sciences, Arizona State University, Tempe, United StatesSanford Burnham Prebys Medical Discovery Institute, La Jolla, United StatesSchool of Molecular Sciences, Arizona State University, Tempe, United StatesSchool of Molecular Sciences, Arizona State University, Tempe, United StatesCenter for Biological Physics and Department of Physics, Arizona State University, Tempe, United StatesWe develop integrated co-evolution and dynamic coupling (ICDC) approach to identify, mutate, and assess distal sites to modulate function. We validate the approach first by analyzing the existing mutational fitness data of TEM-1 β-lactamase and show that allosteric positions co-evolved and dynamically coupled with the active site significantly modulate function. We further apply ICDC approach to identify positions and their mutations that can modulate binding affinity in a lectin, cyanovirin-N (CV-N), that selectively binds to dimannose, and predict binding energies of its variants through Adaptive BP-Dock. Computational and experimental analyses reveal that binding enhancing mutants identified by ICDC impact the dynamics of the binding pocket, and show that rigidification of the binding residues compensates for the entropic cost of binding. This work suggests a mechanism by which distal mutations modulate function through dynamic allostery and provides a blueprint to identify candidates for mutagenesis in order to optimize protein function.https://elifesciences.org/articles/67474protein dynamicsallosterylectinglycanenzymemolecular mechanism |
| spellingShingle | I Can Kazan Prerna Sharma Mohammad Imtiazur Rahman Andrey Bobkov Raimund Fromme Giovanna Ghirlanda S Banu Ozkan Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations eLife protein dynamics allostery lectin glycan enzyme molecular mechanism |
| title | Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations |
| title_full | Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations |
| title_fullStr | Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations |
| title_full_unstemmed | Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations |
| title_short | Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations |
| title_sort | design of novel cyanovirin n variants by modulation of binding dynamics through distal mutations |
| topic | protein dynamics allostery lectin glycan enzyme molecular mechanism |
| url | https://elifesciences.org/articles/67474 |
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