Protein Engineering, Vol. 13, No. 12, 849-856,
December 2000
© 2000 Oxford University Press
PoPMuSiC, an algorithm for predicting protein mutant stability changes. Application to prion proteins
Ingénierie Biomoléculaire, Université Libre de Bruxelles, CP 165/64,50 avenue Roosevelt, 1050 Brussels, Belgium
A novel tool for computer-aided design of single-site mutations in proteins and peptides is presented. It proceeds by performing in silico all possible point mutations in a given protein or protein region and estimating the stability changes with linear combinations of database-derived potentials, whose coefficients depend on the solvent accessibility of the mutated residues. Upon completion, it yields a list of the most stabilizing, destabilizing or neutral mutations. This tool is applied to mouse, hamster and human prion proteins to identify the point mutations that are the most likely to stabilize their cellular form. The selected mutations are essentially located in the second helix, which presents an intrinsic preference to form ß-structures, with the best mutations being T183
F, T192A and Q186A. The T183 mutation is predicted to be by far the most stabilizing one, but should be considered with care as it blocks the glycosylation of N181 and this blockade is known to favor the cellular to scrapie conversion. Furthermore, following the hypothesis that the first helix might induce the formation of hydrophilic ß-aggregates, several mutations that are neutral with respect to the structure's stability but improve the helix hydrophobicity are selected, among which is E146L. These mutations are intended as good candidates to undergo experimental tests.
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