Figure 1.
Structure of LEDGINs and HIV-1 IN CCD dimer.
(A) Chemical structures of BI-1001 and CX14442. (B) Crystal structure of BI-1001 bound to the HIV-1 IN CCD dimer interface (PDB ID code 4DMN). The monomers are distinguished in yellow and cyan, and the BI-1001 is shown in gray stick model. The constructed missing loop (residues 141 to 151) is colored gray. The allosteric site at the HIV-1 IN CCD dimer interface is represented by surface. HIV-1 IN active site residues (Asp64, Asp116, and Glu152) are shown in cyan stick.
Table 1.
Summary of the simulation systems.
Figure 2.
Comparison of the computational docking of CX14442 in the HIV-1 IN CCD dimer versus the reported crystal structure of BI-1001 bound in HIV-1 IN CCD dimer (PDB ID code 4DMN).
The protein is shown in the cartoon representation; the two monomers are colored yellow and cyan, respectively. The LEDGINs are represented in gray stick. Hydrogen bond interactions are denoted by dotted green lines.
Figure 3.
The monitored RMSD of the backbone atoms of protein (black), backbone atoms of binding pocket residues around 5 Å of ligand (blue), and the heavy atoms in the ligand (red) for: (A) BI-1001 and (B) CX14442 bound HIV-1 IN complexes with respect to the initial structures as a function of time.
(C) The monitored RMSD of the backbone atoms of HIV-1 IN and LEDGF/p75 (black), backbone atoms of HIV-1 IN (blue), and backbone atoms of LEDGF/p75 (red) for LEDGF/p75 bound HIV-1 IN complex with respect to the initial structures as a function of time.
Figure 4.
Structural models of (A) BI-1001, (B) CX14442 in complex with HIV-1 IN CCD dimer.
The averaged structures extracted from the MD trajectories were used. The proteins are shown in cartoon representation with two monomers in yellow and cyan. The BI-1001 and CX14442 are shown in gray stick model. Hydrogen bond interactions are denoted by dotted green or blue lines.
Figure 5.
Electrostatic potential surface of the allosteric binding pocket of HIV-1 IN CCD dimer in interaction with (A) BI-1001, (B) CX14442, and (C) LEDGF/p75.
The positive charges are displayed in blue, negative charges are displayed in red, and neutral residues are displayed in white. Color intensity is proportional to the charge value. The BI-1001, CX14442 and side chain of the LEDGF/p75 key residues, whose carbon atoms are shown as green spheres and labeled as red. The residue Trp131 from monomer A of HIV-1 CCD dimer is also labeled (black).
Figure 6.
Per-residue interaction spectrum of the residues of HIV-1 IN CCD with (A) BI-1001, (B) CX14442, and (C) LEDGF/p75 in complex with the HIV-1 IN CCD dimer from MM/GBSA free energy decomposition analysis.
Figure 7.
The generated pharmacophore for HIV-1 IN LEDGINs based on the receptor-ligand interactions.
The model consists of hydrophobic and hydrophilic features on LEDGINs as well as the key residue in HIV-1 IN allosteric site. The hydrophobic and hydrophilic domains are shown in green and red, respectively. The residues that participated in the interaction between LEDGINs and HIV-1 IN CCD are labeled in cyan and orange, while the potential residues used for further extension LEDGINs design are labeled in black and gray.
Figure 8.
The LEDGF/p75 protein residues contribution to the total binding free energy of the LEDGF/p75 bound HIV-1 IN CCD complex.
Figure 9.
Structural model of LEDGF/p75 in complex with HIV-1 IN CCD dimer.
The averaged structure extracted from the MD trajectory was used. The protein is shown in cartoon representation with two monomers in yellow and cyan. The side chains of the LEDGF/p75 amino acids are shown as gray sticks. Hydrogen bond interactions are denoted by dotted green lines.
Table 2.
The free energies calculated by the MM/PBSA methods for binding of BI-1001, CX14442, and LEDGF/p75 to the HIV-1 IN.
Figure 10.
The aligned representative conformations of BI-1001, CX14442, and LEDGF/p75 bound HIV-1 IN CCD dimer models.
The averaged structures extracted from the MD trajectories were used. The BI-1001, CX14442, and LEDGF/p75 bound form are shown in yellow, cyan and gray, respectively. HIV-1 IN active site residues (Asp64, Asp116, and Glu152) are shown in stick. The LEDGINs and LEDGF/p75 are represented in stick and carton, respectively.
Figure 11.
Scheme of the active site DDE motif (Asp64, Asp116, and Glu152) models for (A) LEDGF/p75, (B) BI-1001 and (C) CX14442 bound HIV-1 IN complexes.
The measured distances between the centroid of the side chains of the three conserved catalytic residues were labeled in each model.