I have been running some computational ALA scanning trials on protein-protein complex structures using the FoldX package. In many of my results, a number of residues had negative values of mutation energy. This might seem like a dumb question but: should these results be taken as absolute values, when comparing with a cutoff for the energy change? For example: if I set a cutoff value of 1.0 kcal/mol, and I get DeltaDeltaG=1.8 kcal/mol for M49 and -2.3 kcal/mol for F345, should I interpret both of these residues as "hot spots"?
@ Foltis Should these results be taken as absolute values, when comparing with a cutoff for the energy change?
Yes and No. The FoldX force-field is meant in theory to be an absolute energy scale with del del G (Foldx) = del del G (Exp.) In practice, unless the crystal structure is really good, mutations to alanine will tend to have favorable free energy changes, since side-chain clashes which tend to dominate the energy are lessened. This can be partly alleviated by using the opt function in Fold-X to remove some of the unfavorable interactions. However, I would focus less on the absolute changes and more on the deviation from the baseline level in Ala scan of the protein.
Predicting Changes in the Stability of Proteins and Protein Complexes: A Study of More Than 1000 Mutations
http://www.sciencedirect.com/science/article/pii/S0022283602004424
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