6EZF

PDE2 in complex with molecule 5

Summary for 6EZF

• Entry DOI: 10.2210/pdb6ezf/pdb
• Descriptor: cGMP-dependent 3',5'-cyclic phosphodiesterase, MAGNESIUM ION, ZINC ION, ... (8 entities in total)
• Functional Keywords: pde2, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42041.46

Authors

Tresadern, G.,Perez-Benito, L.,Keraenen, H.,van Vlijmen, H. (deposition date: 2017-11-15, release date: 2018-04-04, Last modification date: 2024-05-08)

Primary citation

Perez-Benito, L.,Keranen, H.,van Vlijmen, H.,Tresadern, G.
Predicting Binding Free Energies of PDE2 Inhibitors. The Difficulties of Protein Conformation.
Sci Rep, 8:4883-4883, 2018

PubMed Abstract: A congeneric series of 21 phosphodiesterase 2 (PDE2) inhibitors are reported. Crystal structures show how the molecules can occupy a 'top-pocket' of the active site. Molecules with small substituents do not enter the pocket, a critical leucine (Leu770) is closed and water molecules are present. Large substituents enter the pocket, opening the Leu770 conformation and displacing the waters. We also report an X-ray structure revealing a new conformation of the PDE2 active site domain. The relative binding affinities of these compounds were studied with free energy perturbation (FEP) methods and it represents an attractive real-world test case. In general, the calculations could predict the energy of small-to-small, or large-to-large molecule perturbations. However, accurately capturing the transition from small-to-large proved challenging. Only when using alternative protein conformations did results improve. The new X-ray structure, along with a modelled dimer, conferred stability to the catalytic domain during the FEP molecular dynamics (MD) simulations, increasing the convergence and thereby improving the prediction of ΔΔG of binding for some small-to-large transitions. In summary, we found the most significant improvement in results when using different protein structures, and this data set is useful for future free energy validation studies.

PubMed: 29559702
DOI: 10.1038/s41598-018-23039-5

Experimental method

X-RAY DIFFRACTION (1.5 Å)