Molecular dynamics simulation of the human apo-dihydrofolate reductase: An investigation of an unstable enzyme

Abstract

Structure and dynamics data of the Homo sapiens apodihydrof olate reductase (hDHFR) have been investigated by molecular dynamics (MD) simulation. The MD simulation for a total of 300 ps was performed for the system containing the apo-hDHFR with explicit water molecules. The last 250 ps MD trajectory of the equilibrated system was generated and the 25 sampling structures of the apo-hDHFR were analyzed. The statistical quantities of the simulation reveal significant differences between the apo-enzyme and the complex form. The differences include the mainchain mobility, the solvent accessibility, the secondary structures, the phenylalanine movement and the hydrogen bond may relate to the stability of the enzyme. The tertiary folding from the secondary structure motif reveals a less compact for the apo-enzyme structure with respect to the X-ray structure of the hDHFR-folate complex. In addition, intramolecular hydrogen bond involving the backbone protons dramatically decreases. Comparisons between the unbound and the ligand-bound enzyme obtained from the X-ray, NMR and MD data are discussed.