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

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.

A Bioinformatics Approach to Identify Natural Autoantibodies from Healthy Blood Donors' Sera Reactive with the HCV NS5A-Derived Peptide by Immunoassay

“…The peak frequency in cross-spectrum of these two sequences is at Fourier frequency, F(0.344), and represents the main mutual spectral characteristic, which is the ISM determinant of immunological cross-recognition. Computational deletions based on the ISM algorithm (41,45) allowed us to identify peptide sequences contributing the most to the F(0.344). In iNOS, this sequence encompasses amino acid residues from 58 to 66, and in HCV NS5A from 324 to 331 (Fig.…”

Protein Interface Pharmacophore Mapping Tools for Small Molecule Protein: Protein Interaction Inhibitor Discovery

“…These amino acids could serve as the anchor residues on which to map the pharmacophore features. The usefulness of this kind of simulation was demonstrated by Zhao, et al and Tintori, et al, who could successfully identified the key interactions mimicked by the previously mentioned LEDGINS [103,104]. Since MM/GBSA uses MD as the sampling method it is slow and highly computationally intensive, limiting its use as a first choice for pharmacophore mapping.…”

“…The MM/GBSA method facilitates decomposition of the energetic contributions at the amino acid level in order to give insights into the importance/energetics of the interactions in the PPI complex. Thus, amino acids that significantly contribute to the binding energy of the PPI interface can be considered hotspots for mediating interface recognition and binding [101][102][103][104]. These amino acids could serve as the anchor residues on which to map the pharmacophore features.…”

2-Aminothiazolones as Anti-HIV Agents That Act as gp120-CD4 Inhibitors

“…An appropriate number of counterions (7 Cl Ϫ ions for NL4.3 and 3 Cl Ϫ ions for AD8 complex) were added to neutralize the system, and the complexes were placed in an octagonal box of TIP3P water molecules. The distance between the box walls and the protein was set to 10 Å. MD runs were carried out with a previously validated protocol (32). Before MD simulation, two stages of energy minimization were performed to remove bad contacts.…”