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Updated: Jul 12, 2026
07:08
Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
Protein stability is determined by single-site bias rather than pairwise covariance
Matt Sternke1,2, Katherine W Tripp1, Soumya Prakash Behera1
1T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
Nature Chemical Biology
|July 10, 2026
Summary
Protein sequence alignments reveal biases that inform structure and function. Surprisingly, removing pair correlations maximizes protein stability, while maximizing them enhances enzyme activity, offering insights into protein design.
Area of Science:
- Biophysics
- Computational Biology
- Protein Engineering
Background:
- Protein sequence alignments contain biases related to structure, stability, and function.
- Potts models, incorporating single-site biases and pair correlations, improve predictions of protein fitness, activity, and stability over simpler models.
Purpose of the Study:
- To design protein sequences using a Potts model with varying single-site biases and pair correlations.
- To determine the impact of these designed sequences on protein stability and activity.
Main Methods:
- Utilized a Potts model to generate protein sequences with controlled levels of single-site biases and pair correlations.
- Measured the stability of the designed protein sequences.
- Assessed the activity of designed sequences in three enzyme families.
Main Results:
- Sequences designed to exclude pair correlations exhibited maximal stability.
- Sequences designed to maximize pair correlations showed reduced stability.
- Maximizing pair correlations significantly increased enzyme activity in three tested families.
Conclusions:
- Eliminating covariant residue pairs enhances protein stability, offering a strategy for protein design.
- This increased stability may come at the cost of reduced enzyme activity.
- Pair correlations appear to contribute to aspects of protein fitness beyond stability, such as catalytic activity.
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