The Monoclonal Antibody Pembrolizumab Alters Dynamics of the Human Programmed Cell Death Receptor 1 (PD-1)

The human immunologic checkpoint receptor PD-1 is an important component within the pathways responsible for the downregulation of the immune system, preventing the targeting of normal host tissues when PD-1 is bound to its endogenous ligand PD-L1. However, PD-L1 is frequently overexpressed in various tumors, allowing these cancers to escape the immune system surveillance. Competitive blocking of the PD-1/PD-L1 interaction with monoclonal antibodies, such as pembrolizumab, has shown great potential for therapeutic interventions. We performed extended molecular dynamics simulations with a total simulation time of $3.6 \mu \mathrm{s}$, employing three independent 600 ns replicas for both the PD-1/PD-L1 and the PD-1/pembrolizumab complex. We observed differences in the PD-1 receptor with respect to the time course of the RMSD, RMSF, the radius of gyration, the number of hydrogen bonds between PD-1 and its ligands, as well as the solvent accessible surface area and the regions of the essential subspace explored by PD-1. The observed differences in the compactness of PD-1, altered dynamics of PD-1 loops, the changes in the relative occurrences of H-bonds, as well as the different domains of the essential subspace explored by PD-1 upon binding to pembrolizumab may serve as a useful supplementary information for the development of new or the enhancement of already available therapeutic antibodies.