Influence of Ligand Chirality on the Catalytic Efficiency of Human 3-Phosphoglycerate Kinase

Abstract

L-nucleoside analogues form an important class of antiviral and anticancer drug candidates. To be pharmacologically active, they need to be phosphorylated in multiple steps by cellular kinases. Human phosphoglycerate kinase (hPGK) was shown to exhibit low specificity for nucleotide diphosphate analogues and its catalytic efficiency in phosphorylation was also affected. Revealing the mechanism of action and functional motions of hPGK gains importance in in silico drug-design to provide efficient phosphorylation process.To elucidate the effect of ligand chirality on dynamics and catalytic efficiency, molecular dynamics simulations were performed on four different nucleotides (D-/L-ADP and D-/L-CDP) in complex with hPGK and 1,3-bisphospho-D-glycerate (bPG). The simulation results confirm high affinity for the natural substrate (D-ADP), while L-ADP shows only moderate affinity for hPGK. The observed short residence time of both CDP enantiomers at the active site suggests very weak binding affinity which may result in poor catalytic efficiency shown for hPGK with D-/L-CDP. Analysis of the simulations unravels important dynamic conditions for efficient phosphorylation replacing the single requirement of a tight binding. These are: 1) over the strength of the binding, the flexibility of the substrate within the binding site gains importance, especially for the phosphate groups; 2) the hinge bending motion of the domains upon substrates binding should be more correlated and directional, and consequently should imply a lower number of hinge residues; 3) the nucleotide binding site should have an increased flexibility allowing significant dynamic freedoms for the substrates.