title: Molecular Dynamics Simulations of HIV-1 Protease Suggest Different Mechanisms Contributing to Drug Resistance.
abstract: A major problem in the antiretroviral treatment of HIV-infections with protease-inhibitors is the emergence of resistance, resulting from the occurrence of distinct mutations within the protease molecule. In the present work molecular dynamics simulations of an active-site mutation (D30N) and a nonactive-site mutation (N88S) of HIV-1 protease that both directly confer resistance to the protease inhibitor Nelfinavir but not to Amprenavir were performed and compared to wild-type HIV-protease. A decreased interaction energy between protease and Nelfinavir was observed for the D30N mutant giving a plausible explanation for resistance, while the N88S mutation did not significantly affect the interaction energies in the bound form. Structural analysis including both ligand-bound and unliganded HIV-1 proteases revealed that the free N88S mutant protease shows significant differences in its hydrogen bonding pattern compared to free or Nelfinavir-bound wild-type protease. In particular, Asp30 forms more frequently a hydrogen bond with Ser88 in the unbound N88S mutant thus interfering with the Asp30-Nelfinavir interaction. These findings suggest that different molecular mechanisms contribute to resistance in active-site and nonactive-site mutants and propose a mechanism for the N88S mutant that is based on a shift of the conformational equilibrium of the unbound protease.
authors.affiliation: Abteilung Bioinformatik, Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wartha
authors.affiliation: Abteilung Bioinformatik, Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany.
authors.forename: Anselm H C
authors.initials: AH
authors.lastname: Horn
authors.affiliation: Abteilung Bioinformatik, Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Meiselbach
authors.affiliation: Abteilung Bioinformatik, Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht