HIV-1 protease molecular dynamics of a wild-type and of the V82F/I84V mutant: Possible contributions to drug resistance and a potential new target site for drugs

Authors

  • Alexander L. Perryman,

    1. Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093-0365, USA
    2. Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0365, USA
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  • Jung-Hsin Lin,

    1. School of Pharmacy, National Taiwan University, Taipei, Taiwan
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  • J. Andrew McCammon

    Corresponding author
    1. Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093-0365, USA
    2. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093-0365, USA
    • University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0365, USA; fax: (858) 534-7042.
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Abstract

The protease from type 1 human immunodeficiency virus (HIV-1) is a critical drug target against which many therapeutically useful inhibitors have been developed; however, the set of viral strains in the population has been shifting to become more drug-resistant. Because indirect effects are contributing to drug resistance, an examination of the dynamic structures of a wild-type and a mutant could be insightful. Consequently, this study examined structural properties sampled during 22 nsec, all atom molecular dynamics (MD) simulations (in explicit water) of both a wild-type and the drug-resistant V82F/I84V mutant of HIV-1 protease. The V82F/I84V mutation significantly decreases the binding affinity of all HIV-1 protease inhibitors currently used clinically. Simulations have shown that the curling of the tips of the active site flaps immediately results in flap opening. In the 22-nsec MD simulations presented here, more frequent and more rapid curling of the mutant's active site flap tips was observed. The mutant protease's flaps also opened farther than the wild-type's flaps did and displayed more flexibility. This suggests that the effect of the mutations on the equilibrium between the semiopen and closed conformations could be one aspect of the mechanism of drug resistance for this mutant. In addition, correlated fluctuations in the active site and periphery were noted that point to a possible binding site for allosteric inhibitors.

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