Crucial stages of protein folding through a solvable model: predicting target sites for enzyme-inhibiting drugs.
An exactly solvable model based on the topology of a protein native state is applied to identify bottlenecks and key sites for the folding of human immunodeficiency virus type 1 (HIV-1) protease. The predicted sites are found to correlate well with clinical data on resistance to Food and Drug Administration-approved drugs. It has been observed that the effects of drug therapy are to induce multiple mutations on the protease. The sites where such mutations occur correlate well with those involved in folding bottlenecks identified through the deterministic procedure proposed in this study. The high statistical significance of the observed correlations suggests that the approach may be promisingly used in conjunction with traditional techniques to identify candidate locations for drug attacks.
Micheletti
Cristian
C
International School for Advanced Studies (SISSA/ISAS), I-34014 Trieste, Italy. michelet@sissa.it
Cecconi
Fabio
F
Flammini
Alessandro
A
Maritan
Amos
A
D000596:Amino Acids / Q000737:chemistry / Q000145:classification; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D013223:Statistics as Topic; D013816:Thermodynamics
D000596:Amino Acids; D017320:HIV Protease Inhibitors; D016333:HIV Protease