A base measure of precision for protein stability predictors: structural sensitivity.

The structural sensitivity of stability prediction methods varies greatly and is caused mainly by the models and less by the actual protein structural differences. As a new recommended standard, we therefore suggest that ΔΔG values are evaluated on three protein structures when available and the associated standard deviation reported, to emphasize not just the accuracy but also the precision of the method in a specific study. Our observation that machine-learning methods deemphasize structure may indicate that folded wild-type structures alone, without the folded mutant and unfolded structures, only add modest value for assessing protein stability effects, and that side-chain-sensitive methods overstate the significance of the folded wild-type structure.