A molecular dynamics study of the structural stability of HIV-1 protease under physiological conditions: The role of Na+ ions in stabilizing the active site

Kovalskyy, D., Dubyna, V., Mark, A. E. and Kornelyuk, A. (2005) A molecular dynamics study of the structural stability of HIV-1 protease under physiological conditions: The role of Na+ ions in stabilizing the active site. Proteins-structure Function And Bioinformatics, 58 2: 450-458. doi:10.1002/prot.20304


Author Kovalskyy, D.
Dubyna, V.
Mark, A. E.
Kornelyuk, A.
Title A molecular dynamics study of the structural stability of HIV-1 protease under physiological conditions: The role of Na+ ions in stabilizing the active site
Journal name Proteins-structure Function And Bioinformatics   Check publisher's open access policy
ISSN 0887-3585
Publication date 2005
Sub-type Article (original research)
DOI 10.1002/prot.20304
Volume 58
Issue 2
Start page 450
End page 458
Total pages 9
Place of publication Hoboken
Publisher Wiley-liss
Language eng
Abstract HIV-1 protease is most active under weakly acidic conditions (pH 3.5-6.5), when the catalytic Asp25 and Asp25' residues share 1 proton. At neutral pH, this proton is lost and the stability of the structure is reduced. Here we present an investigation of the effect of pH on the dynamics of HIV-1 protease using MD simulation techniques. MD simulations of the solvated HIV-1 protease with the Asp25/25' residues monoprotonated and deprotonated have been performed. In addition we investigated the effect of the inclusion of Na+ and Cl- ions to mimic physiological salt conditions. The simulations of the monoprotonated form and deprotonated form including Na+ show very similar behavior. In both cases the protein remained stable in the compact, "self-blocked" conformation in which the active site is blocked by the tips of the flaps. In the deprotonated system a Na+ ion binds tightly to the catalytic dyad shielding the repulsion between the COO- groups. Ab initio calculations also suggest the geometry of the active site with the Na+ bound closely resembles that of the monoprotonated case. In the simulations of the deprotonated form (without Na+ ions), a water molecule bound between the Asp25 Asp25' side-chains. This disrupted the dimerization interface and eventually led to a fully open conformation. (C) 2004 Wiley-Liss, Inc.
Keyword Biochemistry & Molecular Biology
Biophysics
HIV-1 protease
molecular dynamics
acidic and neutral pH
positive ions
stabilizing factor
ab initio optimization
Immunodeficiency Virus-1 Protease
Magnetic-resonance Relaxation
Catalytic Aspartyl Groups
Free-energy Calculations
Model-free Approach
Ab-initio
Inhibitor Binding
Orbital Methods
Retroviral Proteases
Chemical Mechanism
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
 
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