Optimal allosteric stabilization sites using contact stabilization analysis
© 2016 Wiley Periodicals, Inc.
| Publié dans: | Journal of computational chemistry. - 1984. - 38(2017), 15 vom: 05. Juni, Seite 1138-1146 |
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| Auteur principal: | |
| Autres auteurs: | , |
| Format: | Article en ligne |
| Langue: | English |
| Publié: |
2017
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| Accès à la collection: | Journal of computational chemistry |
| Sujets: | Journal Article Research Support, N.I.H., Extramural allostery chemical rescue coarse-grained model molecular dynamics protein re-activation protein stabilization Glucuronidase EC 3.2.1.31 |
| Résumé: | © 2016 Wiley Periodicals, Inc. Proteins can be destabilized by a number of environmental factors such as temperature, pH, and mutation. The ability to subsequently restore function under these conditions by adding small molecule stabilizers, or by introducing disulfide bonds, would be a very powerful tool, but the physical principles that drive this stabilization are not well understood. The first problem lies is in choosing an appropriate binding site or disulfide bond location to best confer stability to the active site and restore function. Here, we present a general framework for predicting which allosteric binding sites correlate with stability in the active site. Using the Karanicolas-Brooks Gō-like model, we examine the dynamics of the enzyme β-glucuronidase using an Umbrella Sampling method to thoroughly sample the conformational landscape. Each intramolecular contact is assigned a score termed a "stabilization factor" that measures its correlation with structural changes in the active site. We have carried out this analysis for three different scaling strengths for the intramolecular contacts, and we examine how the calculated stabilization factors depend on the ensemble of destabilized conformations. We further examine a locally destabilized mutant of β-glucuronidase that has been characterized experimentally, and show that this brings about local changes in the stabilization factors. We find that the proximity to the active site is not sufficient to determine which contacts can confer active site stability. © 2016 Wiley Periodicals, Inc |
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| Description: | Date Completed 17.05.2019 Date Revised 12.11.2023 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.24517 |