Impact of Confinement within a Hydrogel Mesh on Protein Thermodynamic Stability and Aggregation Kinetics
dc.contributor.author | Ghassemi, Zahra | |
dc.contributor.author | Leach, Jennie B. | |
dc.date.accessioned | 2024-09-24T08:59:33Z | |
dc.date.available | 2024-09-24T08:59:33Z | |
dc.date.issued | 2024-01-26 | |
dc.description.abstract | Though protein stability and aggregation have been well characterized in dilute solutions, the influence of a confining environment that exists (e.g., in intercellular and tissue spaces and therapeutic formulations) on the protein structure is largely unknown. Herein, the effects of confinement on stability and aggregation were explored for proteins of different sizes, stability, and hydrophobicity when encapsulated in hydrophilic poly(ethylene glycol) hydrogels. Denaturation curves show linear correlations between confinement size (mesh size) and thermodynamic stability, i.e., unfolding free energy and surface area accessible for solvation (represented by m-value). Two clusters of protein types are identifiable from these correlations; the clusters are defined by differences in protein stability, surface area, and aggregation propensity. Proteins with higher stability, larger surface area, and lower aggregation propensity (e.g., lysozyme and myoglobin) are less affected by the confinement imposed by mesh size than proteins with lower stability, smaller surface area, and higher aggregation propensity (e.g., growth hormone and aldehyde dehydrogenase). According to aggregation kinetics measured by thioflavin T fluorescence, confinement in smaller mesh sizes resulted in slower aggregation rates than that in larger mesh sizes. Compared to that in buffer solution, the confinement of a hydrophobic protein (e.g., human insulin) in the hydrogels accelerates protein aggregation. Conversely, the confinement of a hydrophilic protein (e.g., human amylin) in the hydrogels decelerates or prevents aggregation, with the rates of aggregation inversely proportional to mesh size. These findings provide new insights into protein conformational stability in confined microenvironments relevant to various cellular, tissue, and therapeutics scenarios. | |
dc.description.sponsorship | This work was supported by funding from the National Institutes of Health (5R01GM117159). We thank Dr. Theresa A. Good (National Science Foundation) for insightful discussions about protein structure and function. The National Science Foundation provided support for TAG to contribute to this project through their Independent Research and Development program. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. We thank Dr. Tyler Josephson (CBEE, UMBC) for insightful discussions about data analysis. We thank Dr. Zeev Rosenzweig (Chemistry, UMBC) for access to the Spectra Max M5. | |
dc.description.uri | https://pubs.acs.org/doi/full/10.1021/acs.molpharmaceut.3c00677 | |
dc.format.extent | 36 pages | |
dc.genre | journal articles | |
dc.genre | preprints | |
dc.identifier | doi:10.13016/m2liff-wuct | |
dc.identifier.citation | Ghassemi, Zahra, and Jennie B. Leach. “Impact of Confinement within a Hydrogel Mesh on Protein Thermodynamic Stability and Aggregation Kinetics.” Molecular Pharmaceutics 21, no. 3 (March 4, 2024): 1137–48. https://doi.org/10.1021/acs.molpharmaceut.3c00677. | |
dc.identifier.uri | https://doi.org/10.1021/acs.molpharmaceut.3c00677 | |
dc.identifier.uri | http://hdl.handle.net/11603/36340 | |
dc.language.iso | en_US | |
dc.publisher | ACS | |
dc.relation.isAvailableAt | The University of Maryland, Baltimore County (UMBC) | |
dc.relation.ispartof | UMBC Faculty Collection | |
dc.relation.ispartof | UMBC Chemical, Biochemical & Environmental Engineering Department | |
dc.relation.ispartof | UMBC Center for Women in Technology (CWIT) | |
dc.relation.ispartof | UMBC Student Collection | |
dc.relation.ispartof | UMBC Meyerhoff Scholars Program | |
dc.rights | This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Molecular Pharmaceutics, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acs.molpharmaceut.3c00677. | |
dc.title | Impact of Confinement within a Hydrogel Mesh on Protein Thermodynamic Stability and Aggregation Kinetics | |
dc.type | Text | |
dcterms.creator | https://orcid.org/0000-0002-6212-4362 |
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