Molecular dynamics simulation of the gGAPDH–NAD⁺ complex from Trypanosoma cruzi

Abstract

A 50-ns molecular dynamics simulation has been used to study the homotetramer of the enzyme glycosomal glyceraldehyde 3-phosphate dehydrogenase (gGAPDH) complexes, from Trypanosoma cruzi, with nicotinamide adenine dinucleotide (NAD⁺) cofactors in aqueous solution. The root mean square deviation indicates that the overall structure of the homotetramer does not undergo significant change. The largest structural change observed was in the NAD⁺ binding domain of subunit (chain) D; as a consequence, the NAD⁺ cofactor was dislocated from its initial position. However, the other subunits were not affected, suggesting that the gGAPDH enzyme exhibits non-cooperative behaviour. Our simulation estimates that the NAD⁺ binding domain rotates about 4.8° relative to the catalytic domain in the apo–holo form transition. The hydrogen bond analysis reveals that the residues R12, I13, D38 and M39 are essential for gGAPDH–NAD⁺ interaction. Furthermore, two promising cavities to be explored in drug design were found: one formed by residues I13, R12, T197, T199, E336 and Y339, and the other by residues C166, H194, R249, I13, R12, T197, T199, E336 and Y339. The results presented in this paper offer new insight into the search for inhibitors of the gGAPDH enzyme of T. cruzi protozoan.

Keywords:

• molecular dynamics simulation
• T. cruzi
• gGAPDH–NAD⁺
• drug design

Acknowledgements

The authors gratefully acknowledge the financial support provided by FAPESP according to Proc. 07/54381-4. Osmair Vital de Oliveira also wishes to thank CNPq for the award of a scholarship.