Protein stability-based methods
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Amino acid changes can affect protein stability and there are algorithms that attempt to determine this change in folding free energy. In silico tools include:
• MUpro (http://www.ics.uci.edu/~baldig/mutation.html) Cheng J., Randall A., Baldi P. Prediction of Protein Stability Changes for Single-Site Mutations Using Support Vector Machines. Proteins, (2005) 62, (4) 1125-1132.
• FoldX (http://foldx.crg.es/) Schymkowitz, J., Borg, J., Stricher, F., Nys, R., Rousseau, F., Serrano, L. The FoldX web server: an online force field. Nucleic Acids Res. Jul 1;33, W382-8 (2005).
• PoPMuSiC (http://babylone.ulb.ac.be/popmusic/) Dehouck Y., Kwasigroch J.M., Gilis D., Rooman M. PoPMuSiC 2.1: a web server for the estimation of protein stability changes upon mutation and sequence optimality. BMC Bioinformatics (2011) 12(1):151.
• SDM (Site Directed Mutator) (http://www-cryst.bioc.cam.ac.uk/~sdm/sdm.php) Worth, CL, Preissner, R., Blundell, T.L. SDM – a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res.(2011) Jul 39 W215-22, Epub.
These methods have not been developed to predict whether substitutions will be deleterious or simply represent neutral changes. The degree of stability change that can be accommodated will likely vary between different proteins and some marginally destabilising substitutions will occur whilst others will not. As such, stability-based methods are not deemed suitable for the prediction of missense variants.