Abstract
The new cancer immunotherapy has been carried out with an almost messianic zeal, but its molecular basis remains unclear due to the complexity of programmed death ligand 1 (PD-L1) dimerization. In this study, a new and integral multiple dimerization-modes transformation process of PD-L1s (with a new PD-L1 dimerization mode and a new transformation path discovered) and the corresponding mechanism are predicted using theoretical and computational methods. The results of the state analysis show that 5 stable binding states exist in system. A generalized inter-state transformation rate (GITR) theory is also proposed in such multiple-states self-assembly system to explore the kinetic characteristics of inter-state transformation. A “drug insertion” path was identified as the dominant path of the PD-L1 dimerization-modes transformation. Above results can provide supports for both the relative drug design and other multiple-states self-assembly system from the theoretical chemistry perspective.
Highlights
The search for a cure for cancer has been one of the great pursuits of modern science
The crystal structure (PDB ID: 4Z18) was used as the starting structure for the 150 ns all-atom molecular dynamics (MD) simulation (Alder and Wainwright, 1959; Mccammon et al, 1976; Tuckerman and Martyna, 2000) under the condition described as Molecular Dynamics Simulations methods
After visualizing the simulation trajectory using VMD program (Humphrey et al, 1996), it was found that the upper half (IgV domain) of the two programmed death ligand 1 (PD-L1) had a slight oscillating motion of opening and closing, while the lower half (IgC domain) bound tightly all the time
Summary
The search for a cure for cancer has been one of the great pursuits of modern science. The PD-1/PD-L1 target of cancer immunotherapy has already exhibited excellent clinical pharmacological effects. It has been a great success to block the binding of PD-1/ PD-L1 with monoclonal antibody in clinical application (Brahmer et al, 2012; Topalian et al, 2012). The antibody drugs have some inherent disadvantages such as high price, short half-life, poor penetrability and immunogenicity (Chames et al, 2009). These disadvantages can PD-L1 Dimerization Modes Transformation be overcome by the development of small-molecule PD-1/PD-L1 blocking drugs. It is a pity that the development of small-molecule drugs that block the PD-1/PD-L1 pathway is relatively lagging currently, which is mainly due to the lack of in-depth understanding of the interaction mechanism between the small-molecule drugs and the PD-L1s
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