Unraveling the Specific Recognition Between PD-L1 and Engineered CLP002 Functionalized Gold Nanostructures: MD Simulation Studies

PD-L1 (programmed cell death ligand-1) is a protein located on the surface of regulatory cells. It has an immunosuppressive role as it binds specifically to the protein programmed cell death-1 (PD-1), a checkpoint glycoprotein, present on the surface of immune cells such as T and B lymphocytes. Many tumor cells block the immune response by overexpressing PD-L1 on their surface; therefore, targeting PD-L1 represents a powerful strategy that allows tumor localization. To determine the presence of PD-L1 in cells, the use of ad hoc functionalized peptides that bind to PD-L1 can be exploited. One of them is the peptide CLP002 (Trp-His-Arg-Ser-Tyr-Tyr-Thr-Trp-Asn-Leu-Asn-Thr), which, bound to surface-enhanced Raman scattering (SERS) gold nanostructures via a suitable linker, was shown to be highly effective in recognizing MDA-MB-231 breast cancer cells and, importantly, this recognition can be measured by SERS experiments. To characterize, on a molecular scale, the interaction between PD-L1 and peptide functionalized nanostructures, we performed molecular dynamics (MDs) simulations, studying the features of peptide monolayers bound on gold surfaces in the absence and presence of PD-L1. The results obtained allow us to explain why the nature of the linker plays a fundamental role in the binding and why a peptide carrying the same amino acids as CPL002 but with a different sequence (scrambled) is much less active than CLP002. These results open the way to an in silico evaluation of the key parameters that regulate the binding of PD-L1 useful for cancer recognition.