On the Mechanism of Hydrolysis of Phosphate Monoesters Dianions in Solutions and Proteins
Citations Over TimeTop 10% of 2006 papers
Abstract
The nature of the hydrolysis of phosphate monoester dianions in solutions and in proteins is a problem of significant current interest. The present work explores this problem by systematic calculations of the potential surfaces of the reactions of a series of phosphate monoesters with different leaving groups. These calculations involve computational studies ranging from ab initio calculations with implicit solvent models to ab initio QM/MM free energy calculations. The calculations reproduce the observed linear free energy relationship (LFER) for the solution reaction and thus are consistent with the overall experimental trend and can be used to explore the nature of the transition state (TS) region, which is not accessible to direct experimental studies. It is found that the potential surface for the associative and dissociative paths is very flat and that the relative height of the associative and dissociative TS is different in different systems. In general, the character of the TS changes from associative to dissociative upon decrease in the pKa of the leaving group. It is also demonstrated that traditional experimental markers such as isotope effects and the LFER slope cannot be used in a conclusive way to distinguish between the two classes of transition states. In addition it is found that the effective charges of the TS do not follow the previously assumed simple rule. Armed with that experience we explore the free energy surface for the GTPase reaction of the RasGap system. In this case it is found that the surface is flat but that the lowest TS is associative. The present study indicates that the nature of the potential surfaces for the phosphoryl transfer reactions in solution and proteins is quite complicated and cannot be determined in a conclusive way without the use of careful theoretical studies that should, of course, reproduce the available experimental information.
Related Papers
- → Transition States for Glucopyranose Interconversion(2006)71 cited
- → Experimental and Theoretical Multiple Kinetic Isotope Effects for an SN2 Reaction. An Attempt to Determine Transition‐State Structure and the Ability of Theoretical Methods to Predict Experimental Kinetic Isotope Effects(2003)49 cited
- → Solvent Dependent Leaving Group Fluorine Kinetic Isotope Effect in a Nucleophilic Aromatic Substitution Reaction(1996)37 cited
- → Linear free energy relationship and deuterium kinetic isotope effect observed on phospho and thiophosphoryl transfer reactions in some organophosphorous compounds(2014)4 cited
- → Heavy Atom Kinetic Isotope Effects in HCN Elimination from Some Tricyanides in Methanol [1](1978)