THEORETICAL-STUDY OF INHIBITION OF ADENOSINE-DEAMINASE BY (8R)-COFORMYCIN AND (8R)-DEOXYCOFORMYCIN

Molecular dynamics and free energy simulations were performed to exami ne the binding of (8R)-deoxycoformycin and (8R)-coformycin to adenosin e deaminase. The two inhibitors differ only at the 2' position of the sugar ring; the sugar moiety of conformycin is ribose, while it is deo xyribose for deoxycoformycin. The 100 ps molecular dynamics trajectori es reveal that Asp 19 and His 17 interact strongly with the 5' hydroxy l group of the sugar moiety of both inhibitors and appear to play an i mportant role in binding the sugar. The 2' and 3' groups of the sugars are near the protein-water interface and can be stabilized by either protein residues or water. The flexibility of the residues at the open ing of the active site helps to explain the modest difference in bindi ng of the two inhibitors and how substrates/inhibitors can enter an ot herwise inaccessible binding site.