Improving the Accuracy of Protein Thermostability Predictions for Single Point Mutations
Open accessAbstract
Accurately predicting the protein thermostability changes upon single point mutations in silico is a challenge that has implications for understanding diseases as well as industrial applications of protein engineering. Free energy perturbation (FEP) has been applied to predict the effect of single point mutations on protein stability for over 40 years and emerged as a potentially reliable prediction method with reasonable throughput. However, applications of FEP in protein stability calculations in industrial settings have been hindered by a number of limitations, including the inability to model mutations to and from prolines in which the bonded topology of the backbone is modified and the complexity in modeling charge-changing mutations. In this study, we have extended the FEP+ protocol to enable the accurate modeling of the effects on protein stability from proline mutations and from charge-changing mutations. We also evaluated the influence of the unfolded model in the stability calculations using increasingly longer peptides with native sequence and conformations. With the abovementioned improvements, the accuracy of FEP predictions of protein stability over a data set of 87 mutations on five different proteins has drastically improved compared with previous studies, with a mean unsigned error of 0.86 kcal/mol and root mean square error of 1.11 kcal/mol, comparable with the accuracy of previously published state-of-the-art small-molecule relative binding affinity calculations, which have been shown to be capable of driving discovery projects.
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Proline mutations have been treated before in protein stability FEP+ with reasonable success.
“Proline mutations have been treated before in protein stability FEP+ with reasonable success [35].”
From Robust prediction of relative binding energies for protein-protein complex mutations using free energy perturbation calculations (2024) · cites this paper as [35]
These results are consistent with previous protein FEP+ results where accuracy has been at or near 1 kcal/mol.
“These results are consistent with previous protein FEP+ results where accuracy has been at or near the 1 kcal/mol level[17,18,35,36,39,40].”
From Robust prediction of relative binding energies for protein-protein complex mutations using free energy perturbation calculations (2024) · cites this paper as [35]
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- Authors
- Duan, J., Lupyan, D., & Wang, L.
- Affiliations
- Schrodinger (United States) (US)
- Corresponding author
- Duan, Jianxin
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 119
- Issue
- 1
- Pages
- 115-127
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC7335905
- OpenAlex
- W3032038485
- Cited by
- 63
- References
- 81
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 9 · 2023: 8 · 2022: 15 · 2021: 10 · 2020: 3
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- protein thermal stability, point mutations, free energy perturbation, proline mutations, protein stability prediction, protein engineering, relative binding affinity
- MeSH terms
- Peptides, Proteins, Thermodynamics, Point Mutation, Entropy, Protein Stability
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