Naslov
The large scale conformational change of the human DPP III – substrate prefers the "closed" form

Autori
Tomić, Antonija ; Gonzalez, Miguel ; Tomić, Sanja

Izvornik
Journal of chemical information and modeling (1549-9596) 52 (2012), 6; 1583-1594

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
metallo-peptidase; human dipeptidyl peptidase III; large scale conformational changes; molecular dynamic simulations; substrate binding; binding free energy

Sažetak
Human dipeptidyl peptidase III (DPP III) is a two domain metallo–peptidase from M49 family. The wide inter–domain cleft and broad substrate specificity suggest that this enzyme could experience significant conformational change. Long (> 100 ns) molecular dynamics (MD) simulations of DPP III revealed large range conformational changes of the protein suggesting the pre-existing equilibrium model for a substrate binding. The binding free energy calculations revealed tighter binding of the preferred synthetic substrate Arg–Arg–2–naphtylamide to the "closed" than to the "open" DPP III conformation. Our assumption that Asp372 plays a crucial role in the large scale inter–domain closure was approved by the MD simulations of the Asp372Ala variant. During the same simulation time the variant remained more "open" than the wild type protein. Apparently, Ala was not as efficient as Asp in establishing the inter–domain interactions. According to the MM–PBSA calculations, the electrostatic component of the free energy of solvation turned out to be higher for the "closed" protein than for its less compact form. However, gain in entropy due to water release from the inter–domain cleft nicely balanced this negative effect.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA