COMP-17. BINDING FREE ENERGY ANALYSIS OF PROGRAMMED CELL DEATH PROTEIN PD1 TO ITS LIGAND PD-L1. (5th November 2018) - Pan, Peter
Abstract: Therapies targeting immune checkpoints such as the programmed cell death protein receptor PD1 pathway represent a step forward for treatment of multiple solid cancers such as non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Despite promising pre-clinical data, anti-PD1 monoclonal antibody nivolumab failed to reach its primary efficacy endpoint in a recent phase III randomized clinical trial, CheckMate-143. One possible barrier in glioblastoma is poor diffusion of large monoclonal antibodies across the blood-brain barrier. Identification of the amino acid residue hot spots in PD1 to PDL1 binding could help guide future efforts towards a small molecular inhibitor. We investigate the binding free energies involved in PD1-PDL1 complex formation with a molecular dynamics approach, and identify the specific amino acid sites important for PD1-PDL1 complex formation. Binding free energies were calculated by Molecular mechanics / generalized Born hydrophobic solvent accessible surface area (MM-GBSA) calculations. The residues on PD-L1 with the largest binding free energy delta between bound and unbound states include Arg 125, Tyr 123, and Arg 113 with -7.3 kcal/mol, -6.5 kcal/mol, and -4.3 kcal/mol respectively (with smaller contributions from Tyr 56, Met 115, Asp 122, Ala 121, Phe 19, and Ile 54), while those for PD1 are Glu 136, Gln 75, and Ile 134 with -5.9 kcal/mol, -5.3 kcal/mol, and -5.0 kcal/mol respectively (with smaller contributions from Ile 126, Tyr 68, Thr 76, Leu 128, Ala 132, and Asn 74). These residues define the core of the binding interface between PD1 and PD-L1.