Domain motions in phosphoglycerate kinase using hierarchical NEIMO molecular dynamics simulations

We examined the large-scale domain motions in the glycolytic enzyme phospho glycerate kinase (PGK) using the hierarchical Newton-Euler inverse mass ope rator (H-NEIMO) molecular dynamics (MD) method. NEIMO is an efficient MD me thod for torsion-only internal coordinate dynamics method. H-NEIMO is an ex tension of the NEIMO method for doing coarse grain MD in which large domain s of a protein are treated as rigid clusters connected by flexible torsion angles. This allows an efficient examination of the low-frequency long time scale motions. We find that with both substrates bound (Phospho glycerate and ATP) on PGK the closed domain structure is more stable than the open do main structure. During the H-NEIMO MD the two domains of the open structure come close together while the N-terminus of helix 14 (namely, Gly-394 in t he R65Q yeast structure) moves close to the ATP derivative, suggesting that it could be involved in the mechanism of phosphoryl transfer. We find that residues 175-183 in the R65Q yeast ternary complex structure are important in triggering the closure of the domains, resulting in a piston-like motio n of helix 7. The domain rotation axis in the all atom Cartesian MD simulat ions is close to that of H-NEIMO MD. The axis of domain rotation in H-NEIMO is also in the same region as the rotation axis between two experimental c rystal structures. Thus, H-NEIMO captures the long time scale motions in ra ther short simulation times. This demonstrates that H-NEIMO is a promising mesoscale coarse grain molecular dynamics technique to determine the low-fr equency long time motions responsible for the function of proteins such as PGK.