Simulação de dinâmica molecular com co-solvente para busca de novos sítios de interação na proteína PD-L1.

Abstract

The immune checkpoint receptor PD-1 and its ligand PD-L1 have been shown to be effective targets to development of monoclonal antibody. The knowledge about the interaction between the systems supports the development of new effective drugs to control tumor cells. In the literature, the PD-L1 mode of binding with PD-1, as well as with antibodies and small molecules are already described. However, it is possible that there are hidden interaction sites, whose exposure occurs only through the presence of ligand (cryptic sites). Research in this area is applied to modulate protein-protein interaction through virtual screening, allosteric modulation, for drug development. In this context, in silico approaches have been explored in search of new interaction sites and, in particular, molecular dynamics simulations are used to understand protein conformational fluctuation in presence of external agents, supporting research in the field of structural biology. The aim of the present study was to analyse PD-L1 protein flexibility parameters, also the definition of a controlled system for screening of PD-L1 protein cryptic sites by simulating molecular dynamics with co-solvents. Our results show that C’’D loop behavior is crucial for changing protein flexibility, as well as determining the transition between different conformational states. A detailed analysis of main chain dihedrals of these loop residues specifically demonstrated that the dihedrals 57ψ and 58ψ were responsible for the difference between coefficient values, addicionaly the value of the angles required for the conformational state transition to occur. To investigate cryptic sites in PD-L1, aromatic co-solvents were more efficient in interacting with the protein. Among them, benzene successfully found an unprecedented site in PD-L1, which differs from the main interaction regions between PD-L1 and inhibitors described in the literature. Thus, we suggests new regions of interaction, with possible use for allosteric regulation, which can be used as targets for the design of new bioactive molecules.