Quantum-Dynamical Picture of a Multistep Enzymatic Process: Reaction Catalyzed by Phospholipase A2

Abstract

A quantum-classical molecular dynamics model (QCMD), applying explicit integration of the time-dependent Schrödinger equation (QD) and Newtonian equations of motion (MD), is presented. The model is capable of describing quantum dynamical processes in complex biomolecular systems. It has been applied in simulations of a multistep catalytic process carried out by phospholipase A(2) in its active site. The process includes quantum-dynamical proton transfer from a water molecule to histidine localized in the active site, followed by a nucleophilic attack of the resulting OH(-) group on a carbonyl carbon atom of a phospholipid substrate, leading to cleavage of an adjacent ester bond. The process has been simulated using a parallel version of the QCMD code. The potential energy function for the active site is computed using an approximate valence bond (AVB) method. The dynamics of the key proton is described either by QD or classical MD. The coupling between the quantum proton and the classical atoms is accomplished via Hellmann-Feynman forces, as well as the time dependence of the potential energy function in the Schrödinger equation (QCMD/AVB model). Analysis of the simulation results with an Advanced Visualization System revealed a correlated rather than a stepwise picture of the enzymatic process. It is shown that an sp(2)--> sp(3) configurational change at the substrate carbonyl carbon is mostly responsible for triggering the activation process.

QUANTUMMECHANICALMETHODS FORENZYMEKINETICS

“…Finally, consideration of multidimensional tunneling contributions is required in calculating the transmission coefficient, particularly for reactions involving hydrogen (H, H + , and H − ) transfer. Although quantum mechanical approaches have been used in various ways for studying condensed-phase systems (24,50), it was only recently that computational studies have fully included all three of these aspects of quantum mechanical effects in calculations including an explicit enzyme environment (48,(51)(52)(53)(54)(55)(56)(57)(58)(59). In what follows, we summarize methods that have been developed by our groups and others for including quantum mechanical contributions in enzyme kinetics modeling.…”

Proton shuttle in green fluorescent protein studied by dynamic simulations

“…Furthermore, proton transfer in proteins is a very important process in enzymatic reactions and bioenergetic processes. However, compared with bulk solution, our understanding of this mechanism is far less complete, and only individual transfer steps (13)(14)(15) or transfer through chains of internal water molecules (16,17) have been considered by simulation methods.…”

Uma perspectiva computacional sobre catálise enzimática

“…Além de um recruzamento não-reativo clássico, τ(T) pode ser alterado por efeitos de solvatação de não-equilíbrio (por exemplo, proveniente de uma distribuição configuracional dos reagentes fora do equilíbrio) e por efeitos quânticos como tunelamento 2,8,41,43,50 . Os efeitos de recruzamento e de não-equilíbrio podem apenas tornar τ(T) menor que um e, usualmente, já são pequenos em solução aquosa.…”

“…Contribuições de até 3 ordens de magnitude para o aumento da velocidade de reações enzimáticas foram atribuídas à dinâmica da proteína, ou seja, às vibrações que amplificam o tunelamento em comparação com a reação em solução, nos sistemas em que uma transferência de hidrogênio (tanto nas formas H + , H neutro e H -) é determinante da velocidade de reação 8,43,50 . As desidrogenases de álcool 47 e de lactato 48 são exemplos de sistemas em que este mecanismo catalítico é observado.…”