Molecular dynamics study of the connection between flap closing and binding of fullerene-based inhibitors of the HIV-1 protease

Zhongwei Zhu, David I. Schuster, Mark Tuckerman

Research output: Contribution to journalArticle

Abstract

The complementary spatial relationship between fullerene C60 and the hydrophobic cavity region of the human immunodeficiency virus (HIV) protease, which houses the active site of the enzyme, has led to the suggestion that fullerene-based derivatives could have potential use as effective HIV protease inhibitors. The ability of such compounds to desolvate the cavity region leads to a strong hydrophobic interaction between the C60 moiety and residues in the cavity region. In this study, the connection between the motion of the so-called flexible flaps of the cavity and favorable binding of a fullerene-based protease inhibitor is explored using multiple-time scale molecular dynamics simulations and free energy techniques. In addition, the effect of the interaction between the C60 moiety and the residues in the cavity region on the water content of the cavity is also investigated. Conformational free energy profiles along a suitably chosen flap opening coordinate show a considerable barrier to flap opening in the presence of the inhibitor, while no such barrier exists for the protease alone. This result is interpreted in terms of a strong hydrophobic interaction between the C60 moiety and the flexible flaps, which cause the latter to close tightly around the inhibitor, thereby expelling water from the cavity and leading to a favorable binding interaction. This interpretation is rationalized by direct analysis of the water content in the cavity in the presence and absence of the inhibitor.

Original languageEnglish (US)
Pages (from-to)1326-1333
Number of pages8
JournalBiochemistry
Volume42
Issue number5
DOIs
StatePublished - Feb 11 2003

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Fullerenes
Flaps
Molecular Dynamics Simulation
Protease Inhibitors
Viruses
Water content
Free energy
Molecular dynamics
HIV-1
Peptide Hydrolases
Hydrophobic and Hydrophilic Interactions
Water
HIV
Derivatives
Catalytic Domain
Computer simulation
Enzymes
fullerene C60

ASJC Scopus subject areas

  • Biochemistry

Cite this

Molecular dynamics study of the connection between flap closing and binding of fullerene-based inhibitors of the HIV-1 protease. / Zhu, Zhongwei; Schuster, David I.; Tuckerman, Mark.

In: Biochemistry, Vol. 42, No. 5, 11.02.2003, p. 1326-1333.

Research output: Contribution to journalArticle

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