Theoretical Investigations On The Mechanism Of Dimerizationmodes Transformation In Programmed Death Ligand-1 Protein

Programmed death ligand-1（PD-L1）is a ligand protein imbedding on the cytomembrane of many kinds of tumor cells.PD-L1 on the surface of tumor cell binds to programmed death protein-1（PD-1）located on the surface of T lymphocytes,which inhibits the immune response of T lymphocytes and makes tumor cells immune escape.Blocking the binding of PD-1/PD-L1 with small molecular drugs is the most promising cancer treatment at present.However,there are relatively few studies on the mechanism of interaction between small molecule drugs and PD-L1,which to a large extent restrains the development of related drugs.It is very significant to study the blocking mechanism of small molecular drugs on PD-1/PD-L1.In this study,the complete mechanism of the small molecular drug BMS-202 regulating the PD-L1 protein dimerization-modes transformation and thus blocking the PD-1/PD-L1 binding was investigated through molecular dynamics simulation and theoretical deduction.In the thermodynamic aspect,the results of state analysis stage showed that there were five different stable PD-L1 binding states in the coexistence system of PD-L1 and BMS-202,among which there were two stable apo form PD-L1 dimerization modes,one stable holo form PD-L1 dimerization mode and two stable binding states which contain a monomer PD-L1 and a drug molecule BMS-202 respectively.In the kinetic aspect: a generalized inter-state transformation rate theory（GITR theory）applying to the complex multi-state self-assembly system,based on three hypotheses（single transition state hypothesis,the hypothesis that the transition states are high energy and low concentration,and the hypothesis that the inter-state transformation of the self-assembly system follows first-order kinetics）and mathematical derivation,is proposed to characterize the kinetics of inter-state transformation in the PD-L1 and BMS-202 coexistence systems.Based on the binding free energy,the calculation results of the potential of mean forces（PMF）of adaptive steered molecular dynamics（ASMD）,and combined with the GITR theory,we finally demonstrate that there is a dominant path— "drug insertion path" in the drug-regulated PD-L1 dimerization mode transformation.In addition,under certain approximation,our GITR theory can give a unified analytical solution of the time-dependent evolution of the concentration of each stable state in a complex multi-state self-assembly network consisting of arbitrary finite stable states,arbitrary finite transition states,arbitrary links between them,and arbitrary kinetic orders.The above findings may provide some theoretical perspective for the blocking mechanism of PD-1/PD-L1 pathway and similar complex multiple-state self-assembly networks.