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. 2022 Jan 24;62(2):359-371.
doi: 10.1021/acs.jcim.1c01143. Epub 2021 Dec 31.

IgG1-b12-HIV-gp120 Interface in Solution: A Computational Study

Didac Martí  1   2 , Carlos Alemán  1   2   3 , Jon Ainsley  1   4 , Oscar Ahumada  5 , Juan Torras  1   2
Affiliations

IgG1-b12-HIV-gp120 Interface in Solution: A Computational Study

Didac Martí et al. J Chem Inf Model. .

Abstract

The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of HIV infection. Understanding the b12-gp120 binding mechanism under physiological conditions may assist the development of more broadly effective antibodies. In this work, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein gp120 of HIV-1 and the IgG1-b12 mAb are studied. Accelerated molecular dynamics (aMD) and ab initio hybrid molecular dynamics have been combined to determine the most persistent interactions between the most populated conformations of the antibody-antigen complex under physiological conditions. The results show the most persistent receptor-binding mapping in the conformations of the antibody-antigen interface in solution. The binding-free-energy decomposition reveals a small enhancement in the contribution played by the CDR-H3 region to the b12-gp120 interface compared to the crystal structure.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Model of the antibody–antigen complex between the IgG1’s Fab domain and gp120 protein of the HIV spike is detailed. The antigen (gp120 protein in orange), the heavy chain (pink), and the light chain (green) of the Fab domain are shown. Also, the CD4-binding loops of antigen (in ice blue), CDR-H1 (cyan), CDR-H2 (red), and CDR-H3 (black) are highlighted in the figure.
Figure 2
Figure 2
Detail of the QM region of the b12–gp120 interface in the QM/MM MD simulation. The zoomed image presents the three CDR-H chain regions of the b12 protein that bind with the gp120 protein (highlighted by means of a licorice representation). Amino acid labels from the H1 region of b12 are shown in green, H2 in red, H3 in pink, and amino acids from gp120 in black.
Figure 3
Figure 3
Potential of mean force (PMF) plots showing the dependence between the free-energy landscape and the (a) root mean square displacement (RMSD), (b) binding free energy (BFE), and (c) buried interface surface of b12–gp120 protein–protein complex (BS). For each PMF, the absolute minimum is also shown (red point). The vertical dashed line represents the averaged value of the x-axis variable along the previous cMD simulation. The RMSD value from the cMD simulation is not shown (out of scale at 2.24 Å).
Figure 4
Figure 4
Plot of the two-dimensional potential of mean force (2D-PMF) is showing the landscape between the binding free energy (BFE) and the (a) root mean square displacement (RMSD) and (b) buried interface surface (BS) of the b12–gp120 protein–protein complex. Absolute minima are marked with a red cross.
Figure 5
Figure 5
Number of contacts by residue along the protein–protein interface of the b12–gp120 system. A residue contact is defined as a distance of less or equal than 4 Å between two atoms of residues located on both sides of the interface with a population greater than 90% among all conformations around the global minimum of the PMF = f(RMSD) profile (free energy lower than 0.1 kcal/mol), which were derived from aMD trajectories. Residues belonging to the CDR regions of both mAbs are shown.
Figure 6
Figure 6
Detail of the interface polar interactions between the spike gp120 protein of HIV virus and the mAb IgG1-b12, derived from QM/MM MD trajectories. (a) HB8(Y100h-D368) left and SB1(E58-K432) right. (b) HB5(Y98-G366) top left, HB7(N100g-G367) bottom left, and HB2(N31-S365) right. (c) HB6(Y98-R419) left and HB3(N31-G367) right. (d) HB4(Y53-M475) left and HB1(S30-G473) right. Residues involved in HB and SB interactions are shown as sticks at the interfaces. Amino acids from three CDRs on the heavy chain of b12 that are involved in interface binding are indicated by H labels in parenthesis. HIV-gp120 is colored orange and the heavy chain of IgG1-b12 is pink.
Figure 7
Figure 7
Representative images of the relevant water-bridged complexes of the b12–gp120 interface: detail of the CD4-binding loop residues from gp120 interacting with (a) N52 (H2), (b) N54 (H2), and (c) Y98 (H3) of the b12 protein. Data derived from the IQMMM conformational set.
Figure 8
Figure 8
Comparison of (a) main interacting residues on the epitope of gp120 and the paratope of the b12 heavy chain. The color range for residue contribution to the BFE: <−2.0 kcal/mol (in bold and highlighted in green), contribution range −1.0: −2.0 kcal/mol (highlighted in green), and contribution range −0.25: −1.0 kcal/mol (highlighted in gray). (b) Surface energy contribution to BFE per residue of RBD complexed with IgG1-b12. Energy contribution is denoted by a color map.
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