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

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.

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.

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.

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.