Role of water in the enzymatic catalysis: study of ATP + AMP -> 2ADP conversion by adenylate kinase

TL;DR

This study uses explicit water interactions to compute a free energy surface of adenylate kinase, revealing a stable intermediate state that reduces energy barriers and influences enzyme conformational dynamics during catalysis.

Contribution

It introduces a novel two-dimensional free energy surface with explicit water interactions, uncovering a stable intermediate state missed by previous implicit solvent models.

Findings

Discovery of a stable half-open-half-closed enzyme state.

Water interactions stabilize key conformational states.

Conformational energy barriers are reduced by about 20 kJ/mol.

Abstract

The catalytic conversion ATP + AMP -> 2ADP by the enzyme adenylate kinase (ADK) involves the binding of one ATP molecule to the LID domain and one AMP molecule to the NMP domain. The latter is followed by a phosphate transfer, and then the release of two ADP molecules. We have computed a novel two dimensional configurational free energy surface (2DCFES), with one reaction coordinate each for the LID and the NMP domain motions, with explicit interactions with water. Our computed 2DCFES clearly reveals the existence of a stable half-open-half-closed (HOHC) intermediate state of the enzyme. Cycling of the enzyme through the HOHC state reduces the conformational free energy barrier for the reaction by about 20 kJ/mol. We find that the stability of the half-open-half-closed state (missed in all earlier studies with implicit solvent model) is largely because of the increase of specific interactions of the polar amino acid side chains with water, particularly with the arginine and the histidine residues. Free energy surface of the LID domain is rather rugged, which can conveniently slow down LID's conformational motion, thus facilitating a new substrate capture after the product release in the catalytic cycle.