PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations
Abstract
:1. Introduction
2. Results and Discussion
2.1. Structural Biology Survey of PD-1/PD-L1
2.2. Development of Antibodies Targeting PD-1/PD-L1
2.3. Structure Complement of PD-1
2.4. The Reliability of Molecular Dynamics Simulations
2.5. Molecular Motion Analysis
2.6. Molecular Recognition
2.7. Binding Free Energy Calculation
2.8. The Role of Solvents in Molecular Recognition
2.9. Inhibition Mechanism and Implications for Drug Design
3. Materials and Methods
3.1. Molecular Dynamics Simulations
3.2. Free Energy Landscape
3.3. Cluster Analysis
3.4. Solvent Accessible Surface Area (SASA) Calculation
3.5. Binding Energy Predication
3.6. Key Residue Scanning
4. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Classification | PDB Codes | Residue Ranges | Substrates | Features |
---|---|---|---|---|
PD-1_apo | 1NPU, 3RRQ, 2M2D | S1-E150 | none | All are monomers with fewer mutation. 3RRQ comes from the human with the resolution of 2.1 Å [24,25]. |
PD-1_antibody | 5GGR, 5GGS, 5JXE, 5B8C, 5WT9 | L25-E146 | Nivolumab, Pembrolizumab | All structures belong to the human and are intact with high-resolution, which can be used to explore the binding mode of PD-1 with antibody inhibitors [18,19,26,27]. |
PD-L1_apo | 3BIS, 3FN3, 4ZI8, 5JDR, 5C3T | M18-A232 | none | All are dimers with resolutions up to 1.8 Å (such as 5CT3). Since there is no substrate information, it is used to investigate conformational changes before binding its inhibitors [12,28,29,30]. |
PD-L1_antibody | 5GGT, 5GRJ, 5JDS, 5X8L, 5X8M | A18-H233 | BMS-936559, avelumab, KN035-Fc, atezolizumab, durvalumab | 5JDS has the complete structure, with no mutation and a high resolution of 1.7 Å. The substrate in 5JDS is a nanobody, being the latest antibody drugs which provides a useful idea for the reconstruction and design of antibodies based on the structure of PD-L1 [19,30,31,32]. |
PD-1/PD-L1 | 3BIK, 3SBW, 4ZQK, 5IUS | D29-I148; A18-L231 | none | 3BIK and 3SBW are mouse PD-1/human PD-L1 complex. 4ZQK is human-derived wild type with high resolution and no mutation, more suitable for the following simulation [12,28,33]. |
PD-L1/PD-L1_ligand | 5J8O, 5J89 5N2D, 5N2F | A18-H142 | BMS-8, BMS-37, BMS-200, BMS-202 | For the first time, the structural information of small molecule inhibitors of PD-L1 was reported. Based on the 5J89 structure, Zak group proposed a possible inhibitory mechanism of PD-L1 small molecule inhibitors [34,35]. |
Targets | Antibodies | Developers | Property |
---|---|---|---|
PD-1 | Nivolumab | Bristol-Myers Squibb | Most of the antibody structures are mainly based on PD-L2 and IgG4. The side effects main lie in destabilizing the complex structure of PD-1/PD-L2. Currently, Nivolumab and Pembrolizumab both were used to treat NSCLC and lymphoma. |
Pembrolizumab | Merck | ||
AMP-224/AMP-514 | GlaxoSmithKline | ||
Pidilizumab | CureTech | ||
BGB-A317 | BeiGene | ||
SHR-1210 | Jiangsu Hengui Medicine | ||
PD-L1 | BMS-936559 | Bristol-Myers Squibb | PD-L1 antibody mainly comes from IgG1 and its side effect is weaker than PD-1 mAbs, which is mainly used for the treatment of advanced solid tumors. Most mAbs are in phase I clinical stage, in which Atezolizumab is approved for clinical use. |
Atezolizumab | Genentech/Roche | ||
Durvalumab | AstraZenerca | ||
Avelumab | Pfizer/Merck | ||
KN035-Fc | Hongqiao I Ins Med | ||
PD-L2 | rHlgM12B7 | Mayo Clinic/NCI | The effect of PD-L2 on T cells is far less than that of PD-L1. There are few reports on mABs of PD-L2. |
Systems | ∆H | T∆S | ∆Gbind | ∆Gexp |
---|---|---|---|---|
PD-1/PD-L1 | −46.64 ± 3.24 | −41.37 ± 1.49 | −5.27 | − |
Nano/PD-L1 | −56.73 ± 5.42 | −42.83 ± 2.68 | −13.90 | −11.38 [30] |
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Sun, X.; Yan, X.; Zhuo, W.; Gu, J.; Zuo, K.; Liu, W.; Liang, L.; Gan, Y.; He, G.; Wan, H.; et al. PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations. Int. J. Mol. Sci. 2018, 19, 1984. https://doi.org/10.3390/ijms19071984
Sun X, Yan X, Zhuo W, Gu J, Zuo K, Liu W, Liang L, Gan Y, He G, Wan H, et al. PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations. International Journal of Molecular Sciences. 2018; 19(7):1984. https://doi.org/10.3390/ijms19071984
Chicago/Turabian StyleSun, Xin, Xiao Yan, Wei Zhuo, Jinke Gu, Ke Zuo, Wei Liu, Li Liang, Ya Gan, Gang He, Hua Wan, and et al. 2018. "PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations" International Journal of Molecular Sciences 19, no. 7: 1984. https://doi.org/10.3390/ijms19071984