Investigation into mechanism of orotidine 5′-monophosphate decarboxylase enzyme by MM-PBSA/MM-GBSA and molecular docking

Abstract

In this work, we studied the binding affinity of orotidine 5′-monophosphate (OMP) and 6-hydroxy-UMP (BMP) for Saccharomyces cerevisiae orotidine 5′-monophosphate decarboxylase (OMPDC) enzyme by using Molecular Mechanics-Poisson–Boltzmann Surface Area (MM-PBSA) and the Molecular Mechanics-Generalised Born Surface Area (MM-GBSA) calculations. In all simulations, Asp91, which is an important residue in the enzyme active site, was considered in both anionic (present in the native form of the enzyme) and neutral states. A series of 10-ns molecular dynamics simulations were performed for the four OMPDC–ligand complexes, two ligand-free enzymes and two free ligands, followed by MM-PBSA/MM-GBSA calculations on the collected snapshots, and molecular docking calculations using the free enzymes and ligands. The results of MM-PBSA/MM-GBSA calculations indicate that all of the OMPDC–ligand complexes form favourable systems in water, which is in agreement with corresponding experimental data. The results of the MM-PBSA and molecular docking methods also showed that OMPDC–BMP complexes, transition state analogue and inhibitor of the OMPDC enzyme have the highest binding affinities. The fact that in the native anionic state BMP shows a higher binding affinity compared with the substrate suggests the contribution of a transition state stabilisation mechanism in the debatable catalytic mechanism of the OMPDC enzyme.

Keywords::

• molecular dynamics simulation
• MM-PBSA/MM-GBSA
• molecular docking
• binding affinity
• orotidine 5′-monophosphate decarboxylase

Acknowledgements

We gratefully acknowledge Rahman Rahman Pour for the great support and very useful enzymology discussions, Dr Majid Erfani Moghaddam for simulating discussions and helpful suggestions and Dr Sara Jambarsang for comments on the statistical works.

This paper is derived from Shirin Jamshidi's PhD thesis in Medical Nanotechnology titled ‘A study of interaction of enzyme with its inhibitory compound by molecular dynamics simulations approach’. H. Rafii-Tabar would like to thank Iran's National Elites Foundation (Bonyad Meli Nokhbegan) for a Research Chair in Computational Nanoneuroscience.

Notes

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