Identification of folding preferences of cleavage junctions of HIV-1 precursor proteins for regulation of cleavability

• Published in: Journal of molecular modeling Vol. 17; no. 2; pp. 391 - 399
• Main Authors: Ode, Hirotaka, Yokoyama, Masaru, Kanda, Tadahito, Sato, Hironori
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-02-2011
• Subjects: Amino Acid Sequence; Binding Sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Computer Simulation; gag Gene Products, Human Immunodeficiency Virus - chemistry; gag Gene Products, Human Immunodeficiency Virus - metabolism; HIV Protease - metabolism; HIV-1 - chemistry; Human Immunodeficiency Virus Proteins - chemistry; Human Immunodeficiency Virus Proteins - metabolism; Molecular Medicine; Original Paper; pol Gene Products, Human Immunodeficiency Virus - chemistry; pol Gene Products, Human Immunodeficiency Virus - metabolism; Protein Folding; Protein Precursors - chemistry; Protein Precursors - genetics; Protein Precursors - metabolism; Protein Structure, Tertiary; Theoretical and Computational Chemistry; HIV-1 protease; Substrate recognition; Homology modeling; Replica exchange molecular dynamics
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-010-0739-z

Human immunodeficiency virus type 1 protease (HIV-1 PR) cleaves two viral precursor proteins, Gag and Gag-Pol, at multiple sites. Although the processing proceeds in the rank order to assure effective viral replication, the molecular mechanisms by which the order is regulated are not fully understood. In this study, we used bioinformatics approaches to examine whether the folding preferences of the cleavage junctions influence their cleavabilities by HIV-1 PR. The folding of the eight-amino-acid peptides corresponding to the seven cleavage junctions of the HIV-1
HXB2
Gag and Gag-Pol precursors were simulated in the PR-free and PR-bound states with molecular dynamics and homology modeling methods, and the relationships between the folding parameters and the reported kinetic parameters of the HIV-1
HXB2
peptides were analyzed. We found that a folding preference for forming a dihedral angle of Cβ (P1)-Cα (P1)- Cα (P1’)-Cβ (P1’) in the range of 150 to 180 degrees in the PR-free state was positively correlated with the 1/K
m
(R = 0.95, P = 0.0008) and that the dihedral angle of the O (P2)-C (P2)- C (P1)- O (P1) of the main chains in the PR-bound state was negatively correlated with k
cat
(R = 0.94, P = 0.001). We further found that these two folding properties influenced the overall cleavability of the precursor protein when the sizes of the side chains at the P1 site were similar. These data suggest that the dihedral angles at the specific positions around the cleavage junctions before and after binding to PR are both critical for regulating the cleavability of precursor proteins by HIV-1 PR.