Strategies for Increasing Protein Stability

Peter G. Chandler, Sebastian S. Broendum, Blake T. Riley, Matthew A. Spence, Colin J. Jackson, Sheena McGowan, Ashley M. Buckle

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Otherpeer-review

2 Citations (Scopus)


The stability of wild-type proteins is often a hurdle to their practical use in research, industry, and medicine. The route to engineering stability of a protein of interest lies largely with the available data. Where high-resolution structural data is available, rational design, based on fundamental principles of protein chemistry, can improve protein stability. Recent advances in computational biology and the use of nonnatural amino acids have also provided novel rational methods for improving protein stability. Likewise, the explosion of sequence and structural data available in public databases, in combination with improvements in freely available computational tools, has produced accessible phylogenetic approaches. Trawling modern sequence databases can identify the thermostable homologs of a target protein, and evolutionary data can be quickly generated using available phylogenetic tools. Grafting features from those thermostable homologs or ancestors provides stability improvement through a semi-rational approach. Further, molecular techniques such as directed evolution have shown great promise in delivering designer proteins. These strategies are well documented and newly accessible to the molecular biologist, allowing for rapid enhancements of protein stability.

Original languageEnglish
Title of host publicationProtein Nanotechnology
Subtitle of host publicationProtocols, Instrumentation, and Applications
EditorsJuliet A. Gerrard, Laura J. Domigan
Place of PublicationNew York, NY
PublisherHumana Press
Number of pages19
ISBN (Electronic)9781493998692
ISBN (Print)9781493998685
Publication statusPublished - 2020

Publication series

NameMethods in Molecular Biology
ISSN (Print)1064-3745
ISSN (Electronic)1940-6029


  • Ancestral reconstruction
  • Consensus design
  • Directed evolution
  • Protein stability
  • Rational design
  • Semi-rational design

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