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Binding thermodynamics and interaction patterns of human purine nucleoside phosphorylase-inhibitor complexes from extensive free energy calculations

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Abstract

Human purine nucleoside phosphorylase (hPNP) plays a significant role in the catabolism of deoxyguanosine. The trimeric protein is an important target in the treatment of T-cell cancers and autoimmune disorders. Experimental studies on the inhibition of the hPNP observe that the first ligand bound to one of three subunits effectively inhibits the protein, while the binding of more ligands to the subsequent sites shows negative cooperativities. In this work, we performed extensive end-point and alchemical free energy calculations to determine the binding thermodynamics of the trimeric protein–ligand system. 13 Immucillin inhibitors with experimental results are under calculation. Two widely accepted charge schemes for small molecules including AM1-BCC and RESP are adopted for ligands. The results of RESP are in better agreement with the experimental reference. Further investigations of the interaction networks in the protein–ligand complexes reveal that several residues play significant roles in stabilizing the complex structure. The most commonly observed ones include PHE200, GLU201, MET219, and ASN243. The conformations of the protein in different protein–ligand complexes are observed to be similar. We expect these insights to aid the development of potent drugs targeting hPNP.

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Acknowledgements

Part of the simulation was performed on the high-performance computing platform of the Center for Life Science (Peking University). Dr. Zhaoxi Sun is supported by the PKU-Boya Postdoctoral Fellowship. We are grateful for many valuable and insightful comments from the anonymous reviewers.

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  1. State Key Laboratory of Precision Spectroscopy, School of Physics and Electronic Science, East China Normal University, Shanghai, 200062, China

    Zhe Huai & Zhaoxi Sun

  2. College of Engineering, Hebei Normal University, Shijiazhuang, 050024, China

    Huaiyu Yang

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  1. Zhe Huai
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Correspondence to Zhaoxi Sun.

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10822_2021_382_MOESM1_ESM.pdf

The variation of \({\langle \frac{\partial U}{\partial }\rangle }_{i}\) along the alchemical pathway, the time-evolution of \({\frac{\partial U}{\partial }|}_{i}\), the time series of secondary structures with two charge schemes, the time series and the average number of hydrogen bonds formed between the ligand and its surroundings in protein–ligand and solvated-ligand systems with two charge schemes, the detailed results of free energy estimates obtained from end-point and alchemical free energy calculations, the relative difference between the ESP produced by the two charge models and the HF ESP, and the comparison of the dipole under two charge schemes are given in the supporting information.. Supplementary file1 (PDF 5039 kb)

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Huai, Z., Yang, H. & Sun, Z. Binding thermodynamics and interaction patterns of human purine nucleoside phosphorylase-inhibitor complexes from extensive free energy calculations. J Comput Aided Mol Des 35, 643–656 (2021). https://doi.org/10.1007/s10822-021-00382-w

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