Reaction Dynamics of ATP Hydrolysis in Actin Determined by ab Initio Molecular Dynamics Simulations

Energy released by the hydrolysis of the high-energy phosphate bond of nucleoside triphosphate (NTP) cofactors is the driving force behind most biological processes. To understand how this energy is used to induce differences in protein structure and function, we examine the transfer of vibrational energy into the nucleotide-bound actin active site immediately after reaction activation. To this end, we perform Born-Oppenheimer molecular dynamics simulations of the active site at the level of density functional theory (DFT) starting at the calculated transition state (TS) structure. Similarly to the mechanism determined in many nucleotide-bound protein systems, the Os-Pγ bond is first elongated. Then, nucleophilic attack of the lytic water on Pγ occurs. Subsequently, protons are transferred in a cycle formed by water molecules, a protein residue, Asp154, and the γ-phosphate group, resulting in the formation of H2PO4(-). To investigate the possible creation of excited vibrational states in the products, power spectra of bond-length autocorrelation functions for relevant bonds within the active site are compared for simulations that start at the TS, at reactants, and at reaction end products. The hydroxyl bond formed in the final proton transfer to the phosphate molecule is observed to exhibit relatively high kinetic energies and large oscillations during reaction. It is also likely that some of the energy released by the reaction is captured by the low-energy stretching vibrations of the phosphoryl bonds of orthophosphate, which oscillate with large amplitudes in nonequilibrium simulations of end products.