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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
Author(s) -
Tintori Cristina,
Veljkovic Nevena,
Veljkovic Veljko,
Botta Maurizio
Publication year - 2010
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22847
Subject(s) - integrase , tetramer , small molecule , protein–protein interaction , chemistry , molecular dynamics , protein structure , dimer , computational biology , biology , biochemistry , enzyme , gene , computational chemistry , organic chemistry
Abstract 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. Proteins 2010. © 2010 Wiley‐Liss, Inc.