De novo computational design of bone morphogenetic protein-2 knuckle binders
| dc.contributor.advisor | Hosseinzadeh, Parisa | |
| dc.contributor.author | Burress-Irving, Ben | |
| dc.date.accessioned | 2024-08-30T19:10:35Z | |
| dc.date.available | 2024-08-30T19:10:35Z | |
| dc.date.issued | 2024 | |
| dc.description | 47 pages | |
| dc.description.abstract | Acute or long-term symptoms of a bone fracture have increased globally at a rate of 70.1% from 1990-2019.[1] Bone morphogenetic protein 2 (BMP-2) is an important driving force in osteogenesis and could be an essential therapeutic for mitigating long-term symptoms associated with nonunion fractures. Recombinant human BMP-2 (rhBMP2) has been approved by the Food and Drug Administration (FDA) as a growth factor for therapeutic use against subtypes of nonunion fractures, but research has shown that required supraphysiological amounts from predominant BMP-2 delivery methods lead to overgrowth of bone among other adverse side effects. Therefore, there is a current heightened research interest on controlling the release kinetics of BMP-2 into a fracture site for safer and more efficient bone regeneration. Computational protein design (CPD) is a promising technique for creating de novo binders to BMP-2. Engineered protein-protein interactions can be utilized to participate in a lower risk, affinity-modulated, delivery system to increase the efficacy and decrease adverse side effects of BMP-2. Using PyRosetta[3] design scripts, and the UO Talapas and Franklin computers, I produced several potential de novo protein binding candidates. I have experimentally tested and validated the top designs while increasing the rate of success with RFDiffusion[4] and ProteinMPNN[5] computational techniques. This thesis overviews the successful de novo design of a protein binder with an equilibrium dissociation constant of 771 nM as measured by biolayer interferometry. | en_US |
| dc.identifier.orcid | 0009-0005-9710-3552 | |
| dc.identifier.uri | https://hdl.handle.net/1794/29892 | |
| dc.language.iso | en_US | |
| dc.publisher | University of Oregon | |
| dc.rights | CC BY-NC-ND 4.0 | |
| dc.subject | Computational protein design | en_US |
| dc.subject | Nonunion fractures | en_US |
| dc.subject | Bone healing | en_US |
| dc.subject | Protein engineering | en_US |
| dc.subject | Rosetta | en_US |
| dc.title | De novo computational design of bone morphogenetic protein-2 knuckle binders | |
| dc.type | Thesis/Dissertation |