Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul 28;24(15):12073.
doi: 10.3390/ijms241512073.

Predicting the Effect of Single Mutations on Protein Stability and Binding with Respect to Types of Mutations

Affiliations

Predicting the Effect of Single Mutations on Protein Stability and Binding with Respect to Types of Mutations

Preeti Pandey et al. Int J Mol Sci. .

Abstract

The development of methods and algorithms to predict the effect of mutations on protein stability, protein-protein interaction, and protein-DNA/RNA binding is necessitated by the needs of protein engineering and for understanding the molecular mechanism of disease-causing variants. The vast majority of the leading methods require a database of experimentally measured folding and binding free energy changes for training. These databases are collections of experimental data taken from scientific investigations typically aimed at probing the role of particular residues on the above-mentioned thermodynamic characteristics, i.e., the mutations are not introduced at random and do not necessarily represent mutations originating from single nucleotide variants (SNV). Thus, the reported performance of the leading algorithms assessed on these databases or other limited cases may not be applicable for predicting the effect of SNVs seen in the human population. Indeed, we demonstrate that the SNVs and non-SNVs are not equally presented in the corresponding databases, and the distribution of the free energy changes is not the same. It is shown that the Pearson correlation coefficients (PCCs) of folding and binding free energy changes obtained in cases involving SNVs are smaller than for non-SNVs, indicating that caution should be used in applying them to reveal the effect of human SNVs. Furthermore, it is demonstrated that some methods are sensitive to the chemical nature of the mutations, resulting in PCCs that differ by a factor of four across chemically different mutations. All methods are found to underestimate the energy changes by roughly a factor of 2.

Keywords: binding free energy change; folding free energy change; mutations; single nucleotide variant.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of change in folding and binding free energy for different datasets.

References

    1. Kent S., Marshall G.R., Wlodawer A. Determining the 3D Structure of HIV-1 Protease. Science. 2000;288:1590. doi: 10.1126/science.288.5471.1590a. - DOI - PubMed
    1. Naddaf M. How Do We Smell? First 3D Structure of Human Odour Receptor Clues. Nature. 2023 ahead of print . - PubMed
    1. Pacheco-Fiallos B., Vorländer M.K., Riabov-Bassat D., Fin L., O’Reilly F.J., Ayala F.I., Schellhaas U., Rappsilber J., Plaschka C. MRNA Recognition and Packaging by the Human-Export Complex. Nature. 2023;616:828–835. doi: 10.1038/s41586-023-05904-0. - DOI - PMC - PubMed
    1. Pradhan B., Kanno T., Umeda Igarashi M., Loke M.S., Baaske M.D., Wong J.S.K., Jeppsson K., Björkegren C., Kim E. The Smc5/6 Complex Is a DNA Loop-Extruding Motor. Nature. 2023;616:843–848. doi: 10.1038/s41586-023-05963-3. - DOI - PMC - PubMed
    1. Bell D.R., Cheng S.Y., Salazar H., Ren P. Capturing RNA Folding Free Energy with Coarse-Grained Dynamics Simulations. Sci. Rep. 2017;7:45812. doi: 10.1038/srep45812. - DOI - PMC - PubMed

LinkOut - more resources