Loop motion and base release in purine-specific nucleoside hydrolase: A molecular dynamics study

Abstract

Although various Trypanosoma vivax purine-specific inosine–adenosine–guanosine nucleoside hydrolase (IAG-NH) crystal structures have been determined and the chemical reaction mechanism of substrate hydrolysis has been studied recently, the mechanistic details for the release of base and ribose are still unclear. Herein molecular dynamics (MD) simulations combined with umbrella sampling technique were utilized to explore the regulation mechanisms of key residues and loops 1 and 2 for the base release. Our results have indicated that the base release process is not the rate-limiting step in the entire hydrolysis process, and the very low barrier of ~5.6kcal/mol can be washed out easily by the notable exothermicity from the substrate hydrolysis step. Moreover, the MD simulations have revealed that Glu82/Trp83 in loop 1 and His247/Arg252 in loop 2 are important to modulate the base release. The partial helix-to-coil change of loop 2 along with the base release process has been observed, showing good agreement with the IAG-NH crystal structures. The local binding site around the ribose after the base release is also discussed.