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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
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De novo design of tunable, pH-driven conformational changes
Scott E Boyken1,2, Mark A Benhaim3, Florian Busch4
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Science (New York, N.Y.)
|May 18, 2019
Summary
Scientists designed pH-responsive proteins that change shape at specific acidity levels. These novel proteins can disrupt cell membranes, showcasing programmable protein conformational changes.
Area of Science:
- Protein engineering
- Biochemistry
- Molecular biology
Background:
- Protein conformational changes are vital for biological functions.
- Designing proteins with switchable conformations is a significant challenge.
- Previous de novo protein design focused on single stable states.
Purpose of the Study:
- To develop a general strategy for designing pH-responsive protein conformational switches.
- To enable precise control over protein structure transitions based on environmental pH.
- To create novel proteins capable of environmentally triggered function.
Main Methods:
- Designing protein structures with preorganized histidine residues in buried hydrogen-bond networks.
- Creating homotrimers and heterodimers with controlled histidine content and hydrophobic interactions.
- Assessing protein stability, conformational changes at varying pH, and membrane disruption capabilities.
Main Results:
- Successfully designed stable homotrimers and heterodimers that undergo large-scale conformational changes below pH 6.5.
- Demonstrated control over transition pH and cooperativity by modulating histidine networks and hydrophobic interactions.
- Observed in vitro and in vivo disruption of lipid membranes by the designed proteins upon disassembly.
Conclusions:
- A general strategy for programming environmentally triggered protein conformational changes via de novo design has been established.
- Designed histidine-based networks enable precise control over pH-responsive protein behavior.
- These engineered proteins show potential for applications requiring targeted membrane disruption.
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