Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: insights from molecular dynamics simulations and the informational spectrum method

Proteins. 2010 Dec;78(16):3396-408. doi: 10.1002/prot.22847. Epub 2010 Sep 27.


A crystal structure of the integrase binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75) in complex with the dimer of the HIV-1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein-protein contacts in HIV-1. However, mutagenic studies indicated that interactions between the full-length proteins were more extensive than the contacts observed in the co-crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full-length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full-length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV-1 IN interactions with cellular co-factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long-range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN-LEDGF/p75 interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology / methods*
  • HIV Integrase / chemistry*
  • HIV Integrase / metabolism*
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Intercellular Signaling Peptides and Proteins / chemistry*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Analysis, Protein / methods*
  • Static Electricity
  • Thermodynamics
  • Time Factors


  • Intercellular Signaling Peptides and Proteins
  • lens epithelium-derived growth factor
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1