Abstract
We have used an ‘activated’ molecular dynamics approach to simulate flap opening in HIV-1 protease. An initial impulse for flap opening was provided by applying harmonic constraints to non-flap residues. After an initial ‘melting’ phase, the two β-hairpin structures that constitute the flaps opened to a 25 Å gap within 200 ps of simulation. Analysis of backbone torsion angles suggests that flap opening is related to conformational changes at Lys 45, Met 46, Gly 52 and Phe 53. In contrast, similar molecular dynamics simulations on the M461 mutant, which is associated with drug resistance, indicates that this mutation stabilizes the flaps in a closed conformation.
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References
Wlodawer, A. & Erickson, J.W. Structure-based inhibitors of HIV-1 protease. A. Rev. Biochem. 62, 543–585 (1993).
Ho, D.D. et al. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J. Virol. 68, 2016–2020 (1994).
Kaplan, A.H. et al. Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proc .natn .Acad. Sci. U.S.A. 91, 5597–5601 (1994).
Harte, W.E., Jr et al. Domain communication in the dynamical structure of human immunodeficiency virus 1 protease. Proc. natn. Acad. Sci. U.S.A. 87, 8864–8868 (1990).
York, D.M., Darden, T.A., Pedersen, L.G. & Anderson, M.W. Molecular dynamics simulation of HIV-1 protease in a crystalline environment and in solution. Biochemistry 32, 1443–1453 (1993).
Wlodawer, A. et al. Conserved folding in retroviral proteases. Crystal structure of a synthetic HIV-1 protease. Science 245, 616 (1989).
Miller, M. et al. Structure of a complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 Å resolution. Science 246, 1149–1152 (1989).
Pearlman, D.A. et al. AMBER 4.0 (San Francisco; 1991).
Wilderspin, A.F. & Sugrue, R.J. Alternative native flap conformation revealed by 2.3 Å resolution structure of SIV proteinase . J. molec. Biol. 239, 97–103 (1994).
Zhao, B. et al. Three-dimensional structure of a simian immunodeficiency virus protease/inhibitor complex. Implications for the design of human immunodeficiency virus type 1 and 2 protease inhibitors. Biochemistry 32, 13054–13060 (1993).
Weiner, S.J., Kollman, P.A., Nguyen, D.T. & Case, D.A. An all atom force field for simulations of proteins and nucleic acids. J. comp. Chem. 7, 230–252 (1985).
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Collins, J., Burt, S. & Erickson, J. Flap opening in HIV-1 protease simulated by ‘activated’ molecular dynamics. Nat Struct Mol Biol 2, 334–338 (1995). https://doi.org/10.1038/nsb0495-334
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DOI: https://doi.org/10.1038/nsb0495-334
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