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Perturbing the energy landscape for improved packing during computational protein design
- Source :
- Proteins
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- The FastDesign protocol in the molecular modeling program Rosetta iterates between sequence optimization and structure refinement to stabilize de novo designed protein structures and complexes. FastDesign has been used previously to design novel protein folds and assemblies with important applications in research and medicine. To promote sampling of alternative conformations and sequences, FastDesign includes stages where the energy landscape is smoothened by reducing repulsive forces. Here, we discover that this process disfavors larger amino acids in the protein core because the protein compresses in the early stages of refinement. By testing alternative ramping strategies for the repulsive weight, we arrive at a scheme that produces lower energy designs with more native-like sequence composition in the protein core. We further validate the protocol by designing and experimentally characterizing over 4000 proteins and show that the new protocol produces higher stability proteins. This article is protected by copyright. All rights reserved.
- Subjects :
- Protein Folding
Molecular model
Protein Conformation
Computer science
Protein design
Stability (learning theory)
Protein Engineering
Energy minimization
Biochemistry
Article
03 medical and health sciences
Protein structure
Structural Biology
Databases, Protein
Molecular Biology
Protocol (object-oriented programming)
030304 developmental biology
0303 health sciences
Sequence
Protein Stability
030302 biochemistry & molecular biology
Computational Biology
Proteins
Energy landscape
Biological system
Hydrophobic and Hydrophilic Interactions
Subjects
Details
- ISSN :
- 10970134 and 08873585
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- Proteins: Structure, Function, and Bioinformatics
- Accession number :
- edsair.doi.dedup.....bedef066eb9c0f2c18fe7ae7ad81da0f
- Full Text :
- https://doi.org/10.1002/prot.26030