Article thumbnail

Visualization of Early Events in Acetic Acid Denaturation of HIV-1 Protease: A Molecular Dynamics Study

By Aditi Narendra Borkar, Manoj Kumar Rout and Ramakrishna V. Hosur


Protein denaturation plays a crucial role in cellular processes. In this study, denaturation of HIV-1 Protease (PR) was investigated by all-atom MD simulations in explicit solvent. The PR dimer and monomer were simulated separately in 9 M acetic acid (9 M AcOH) solution and water to study the denaturation process of PR in acetic acid environment. Direct visualization of the denaturation dynamics that is readily available from such simulations has been presented. Our simulations in 9 M AcOH reveal that the PR denaturation begins by separation of dimer into intact monomers and it is only after this separation that the monomer units start denaturing. The denaturation of the monomers is flagged off by the loss of crucial interactions between the α-helix at C-terminal and surrounding β-strands. This causes the structure to transit from the equilibrium dynamics to random non-equilibrating dynamics. Residence time calculations indicate that denaturation occurs via direct interaction of the acetic acid molecules with certain regions of the protein in 9 M AcOH. All these observations have helped to decipher a picture of the early events in acetic acid denaturation of PR and have illustrated that the α-helix and the β-sheet at the C-terminus of a native and functional PR dimer should maintain both the stability and the function of the enzyme and thus present newer targets for blocking PR function

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2001). 1.9 A ˚ x-ray study shows closed flap conformation in crystals of tethered HIV-1
  2. (1998). A cooperative folding unit in HIV-1 protease, Implications for protein stability and occurrence of druginduced mutations.
  3. (2001). An improved GROMOS96 force field for aliphatic hydrocarbons in the condensed phase.
  4. (2003). Caflisch A
  5. (2005). Design of HIV-1 PR inhibitors that do not create resistance: blocking the folding of single monomers.
  6. (1983). Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features.
  7. (2001). Distributions of intramolecular distances in the reduced and denatured states of bovine pancreatic ribonuclease A. Folding initiation structures in the C-terminal portions of the reduced proteins.
  8. (1995). Flap opening in HIV-1 protease simulated by ‘activated’ molecular dynamics.
  9. (2009). Fluctuating partially native-like topologies in the acid denatured ensemble of autolysis resistant HIV-1 protease.
  10. (2002). Folding and design of dimeric proteins.
  11. (2005). Folding regulates the autoprocessing of HIV-1 protease precursor.
  12. (2001). GROMACS 3.0: a package for molecular simulation and trajectory analysis.
  13. (1995). GROMACS: a message-passing parallel molecular dynamics implementation.
  14. (2006). HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations.
  15. (2004). 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.
  16. (2007). HIV-1 Protease Substrate Binding and Product Release Pathways Explored with CoarseGrained Molecular Dynamics.
  17. (1981). Interaction models for water in relation to protein hydration in Intermolecular forces,
  18. (2004). Molecular dynamics simulations of 14 HIV protease mutants in complexes with indinavir.
  19. (2008). Molecular dynamics simulations of HIV-1 protease monomer: Assembly of N-terminus and Cterminus into b-sheet in water solution.
  20. (2005). Molecular Dynamics Simulations of HIV-1 Protease Suggest Different Mechanisms Contributing to Drug Resistance.
  21. (1994). Molecular dynamics simulations of HIV-1 protease with peptide substrate.
  22. (2003). Molecular Dynamics Study of the Connection between Flap Closing and Binding of Fullerene-Based Inhibitors of the HIV-1 Protease.
  23. (2000). NMR characterization of residual structure in the denatured state of protein L.
  24. (2003). NMR elucidation of early folding hierarchy in HIV-1 protease.
  25. (2001). NMR identification of local structural preferences in HIV-1 protease tethered heterodimer in 6 M guanidine hydrochloride.
  26. (1999). NOE data demonstrating a compact unfolded state for an SH3 domain under non-denaturing conditions.
  27. (2004). PRODRG - a tool for highthroughput crystallography of protein-ligand complexes.
  28. (2003). Solution structure of the mature HIV-1 protease monomer: Insight into the tertiary fold and stability of a precursor.
  29. (1995). Structural characterization of folded and unfolded states of an SH3 domain in equilibrium in aqueous buffer.
  30. (2004). The folding and dimerization of HIV-1 Protease: Evidence for a stable monomer from simulations.
  31. Tiana G (2001a) Hierarchy of events in the folding of model proteins.
  32. Tiana G (2001b) Reading the three-dimensional structure of latticed model-designed proteins from their amino acid sequence.
  33. (2004). VEGA - An open platform to develop chemo-bio-informatics applications using plug-in architecture and script programming.
  34. (1996). VMD - Visual Molecular Dynamics.