D. Gilis et M. Rooman, PoPMuSiC, an algorithm for predicting protein mutant stability changes. Application to prion proteins, PROTEIN ENG, 13(12), 2000, pp. 849-856
A novel tool for computer-aided design of single-site mutations in proteins
and peptides is presented. It proceeds by performing in silico all possibl
e point mutations in a given protein or protein region and estimating the s
tability changes with linear combinations of database-derived potentials, w
hose coefficients depend on the solvent accessibility of the mutated residu
es, Upon completion, it yields a list of the most stabilizing, destabilizin
g or neutral mutations, This tool is applied to mouse, hamster and human pr
ion proteins to identify the point mutations that are the most likely to st
abilize their cellular form. The selected mutations are essentially located
in the second helix, which presents an intrinsic preference to form p-stru
ctures, with the best mutations being T183 -->F, T192 -->A and Q186 -->A. T
he T183 mutation is predicted to be by far the most stabilizing one, but sh
ould be considered with care as it blocks the glycosylation of N181 and thi
s blockade is known to favor the cellular to scrapie conversion. Furthermor
e, following the hypothesis that the first helix might induce the formation
of hydrophilic P-aggregates, several mutations that are neutral with respe
ct to the structure's stability but improve the helix hydrophobicity are se
lected, among which is E146 -->L. These mutations are intended as good cand
idates to undergo experimental tests.