Importance of an Orchestrate Participation of each Individual Residue Present at a Catalytic Site

Abstract

GTP hydrolysis is indispensable to keep a living cell healthy. Nature has evolved so many enzymes to enhance the slow GTP hydrolysis. Rab GTPases are evolved to regulate vesicle trafficking. GTPase activating proteins (GAPs) accelerates their intrinsic slow GTP hydrolysis in order to maintain the sustainability between cellular events. Any malfunction/interference in this hydrolysis disrupts normal cellular events and causes severe diseases. In this study, GTP hydrolysis mechanism of Rab33B catalyzed by TBC-domain GAP protein Gyp1p has been decoded using extensive ab initio QM/MM metadynamics simulations. An organized coupled movement of individual residues present at the catalytic site is found to be the key factor for this reaction. An unorganized coupled movement leads the hydrolysis through very high energy pathways. This also reveals that the chemical transformations occurring at a catalytic site are residue specific.

Keywords: Metadynamics; Phosphate-ester Hydrolysis; QM/MM; Rab GTPase; TBC-Domain GAP.