Study of orotidine 5′-monophosphate decarboxylase in complex with the top three OMP, BMP, and PMP ligands by molecular dynamics simulation

Abstract

Catalytic mechanism of orotidine 5′-monophosphate decarboxylase (OMPDC), one of the nature most proficient enzymes which provides large rate enhancement, has not been fully understood yet. A series of 30 ns molecular dynamics (MD) simulations were run on X-ray structure of the OMPDC from Saccharomyces cerevisiae in its free form as well as in complex with different ligands, namely 1-(5′-phospho-D-ribofuranosyl) barbituric acid (BMP), orotidine 5′-monophosphate (OMP), and 6-phosphonouridine 5′-monophosphate (PMP). The importance of this biological system is justified both by its high rate enhancement and its potential use as a target in chemotherapy. This work focuses on comparing two physicochemical states of the enzyme (protonated and deprotonated Asp91) and three ligands (substrate OMP, inhibitor, and transition state analog BMP and substrate analog PMP). Detailed analysis of the active site geometry and its interactions is properly put in context by extensive comparison with relevant experimental works. Our overall results show that in terms of hydrogen bond occupancy, electrostatic interactions, dihedral angles, active site configuration, and movement of loops, notable differences among different complexes are observed. Comparison of the results obtained from these simulations provides some detailed structural data for the complexes, the enzyme, and the ligands, as well as useful insights into the inhibition mechanism of the OMPDC enzyme. Furthermore, these simulations are applied to clarify the ambiguous mechanism of the OMPDC enzyme, and imply that the substrate destabilization and transition state stabilization contribute to the mechanism of action of the most proficient enzyme, OMPDC.

Keywords:

• molecular dynamics
• enzyme–ligand interaction
• substrate destabilization
• transition state stabilization
• orotidine 5′-monophosphate decarboxylase

Acknowledgment

We gratefully acknowledge Rahman Rahman Pour for his help about enzyme mechanisms and all of his great supports, Dr. Majid Erfani Moghaddam and Dr. Ali Razazan for simulating discussions and helpful suggestions, Dr. Sara Jambarsang for comments on the statistical work and advice on R programming and special thanks for Dr. Mohammadali Rezaei for proof reading. H. Rafii-Tabar would like to thank Iran’s National Elites Foundation (Bonyad meli Nokhbegan) for a research Chair in Computational Nanoneuroscience.

Notes

This paper is derived from Shirin Jamshidi’s PhD thesis in Medical Nanotechnology titled “A study of interaction of ODCase enzyme with its inhibitory compounds, BMP and PMP, by molecular dynamics simulations approach”.