Mapping the epitope of PD-L1 to the paratope of the antibody durvalumab using molecular dynamics simulation

Abstract

Objectives: Durvalumab, a human monoclonal antibody that stops PD-L1 from attaching itself to CD80 and PD-1, was approved by the Food and Drug Administration for use in cancer therapy. An essential stage in antibody optimization is mapping paratope residues to epitope residues. In this study, our earlier computer-aided method based on molecular dynamics (MD) simulations was used to observe the paratope residues on durvalumab and their companions on PD-L1.

Methods: The durvalumab/PD-L1 complex model was obtained from the Protein Data Bank and used in a rectangular box for solvation. On durvalumab, the paratope residues and their companions on PD-L1 were identified using MD simulations. The interface residues were ranked on the basis of their contributions to the binding of durvalumab and PD-L1 by assessing the stability of hydrogen bonds and salt bridges. This assessment was conducted using free and guided MD simulations.

Results: Seventeen residues, including ASP26, GLU58, GLU60, ASP61, ARG113, ARG125, and THR127 on PD-L1 and H31ARG, H52LYS, H53GLN, H57GLU, H99GLU, H103PHE, H113ARG, L28ARG, L31SER, and L92TYR on durvalumab, were expected to be necessary for the binding of durvalumab to PD-L1. ASP26, ARG113, and ARG125 on PD-L1 were essential for its binding to PD-1. Eight residues (GLU60, ASP61, and THR127 on PD-L1 and L31SER, H99GLU, H53GLU, H31ARG, and H113ARG on durvalumab) were newly found, and two residues (LYS124 on PD-L1 and L94SER on durvalumab) proven nonessential for complexation, compared to the findings from the examined crystal structure.

Conclusions: The antithrombotic antibody of durvalumab's paratope may be effectively mapped to the PD-L1 epitope using the existing computer method. This information will help optimize durvalumab.

Keywords: Durvalumab; MD simulations; PD-L1; epitope; paratope.

Figure 1

Flow chart of free and steered MD simulations. MD, molecular dynamics.

Figure 2

Variation of the RMSD of heavy atoms of durvalumab/PD-L1 complex versus simulation time. I, II, and III denote three independent system equilibrium processes.

Figure 3

Time courses of interatomic distances of six representative bonds in binding site of durvalumab/PD-L1 complex. The interatomic distances of six representative bonds were plotted against simulation time, where the interatomic distances were from donors to their respective acceptors for three hydrogen bonds. The hydrogen bonds were simulated with the initial conformation I (FMD1_1~FMD1_3). The black dashed line expresses the distance cut-off of 0.35 nm beyond which the bonds breaks, and the blue, green and red lines exhibit the variation of interatomic distances of a bond against simulation time for thrice-repeat independent free MD simulations, respectively. The thermal stabilizations of the No. 8 and 9 bonds seemed to be higher than those of the No. 21 and 22 bonds but lower than those of the No. 1 and 4 bonds. Significant differences in the thrice-repeat independent simulations showed a random behavior of intermolecular interactions.

Figure 4

Predicted interaction residues on the interface of the durvalumab/PD-L1 complex by molecular dynamics simulation. A. The durvalumab/PD-L1 complex; B. The predicted epitope residues on PD-L1; C. The predicted paratope residues on durvalumab. PD-L1 is shown in yellow and durvalumab is presented in gray. Predicted residues were shown in red with name labelled. All interaction residues on the interface of durvalumab/PD-L1 complex were predicted in terms of the mean survival ratio, normalized mean rupture time, or HBSI index.

Figure 5

Variation of interatomic distance versus steered simulation time. The interatomic distances of the six representative bonds under stretching were plotted against simulation time, where all descriptions for line types, bonds and their lengths are same as those in Figure 2. These time courses of interatomic distances showed that, the No. 21 and 22 bonds were very quickly ruptured, in comparison to others, in which the No. 1 and 4 bonds maintained longer duration than the No. 8 and 9 bonds.