Toward an Automatic Determination of Enzymatic Reaction Mechanisms and Their Activation Free Energies

Abstract

We present a combination of the string method and a path collective variable for the exploration of the free energy surface associated to a chemical reaction in condensed environments. The on-the-fly string method is employed to find the minimum free energy paths on a multidimensional free energy surface defined in terms of interatomic distances, which is a convenient selection to study bond forming/breaking processes. Once the paths have been determined, a reaction coordinate is defined as a measure of the advance of the system along these paths. This reaction coordinate can be then used to trace the reaction Potential of Mean Force from which the activation free energy can be obtained. This combination of methodologies has been here applied to the study, by means of Quantum Mechanics/Molecular Mechanics simulations, of the reaction catalyzed by guanidinoacetate methyltransferase. This enzyme catalyzes the methylation of guanidinoacetate by S-adenosyl-L-methionine, a reaction that involves a methyl transfer and a proton transfer and for which different reaction mechanisms have been proposed.

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

“…Unique in this approach was the construction of a single composite MD system containing 27 individual β2 molecules restrained to points on 3 × 3 × 3 grid inside a single large solvent box. Zinovjev et al used a combination of the on-the-fly string method and of path-collective variables (see Equations (28) and (29)) in a quantum-mechanics/molecular-mechanics approach to study a methyltransferase reaction [234].…”

Unraveling the Reaction Mechanism of Enzymatic C5-Cytosine Methylation of DNA. A Combined Molecular Dynamics and QM/MM Study of Wild Type and Gln119 Variant

“…These computational levels have been shown to produce good results in the study of other methyltransferases. 44,55 These calculations were done with an interface between fDynamo and Gaussian09.…”

“…This approach has already shown to be successful for the analysis of several complex enzymatic reactions. 44,55 In our calculations the coordinates used to trace the MFEP included all the interatomic distances associated with all possible bond breaking and forming events that could take place at each reaction step. Therefore no a priori assumptions have to be made about the reaction mechanism.…”

Exploring chemical reactivity of complex systems with path‐based coordinates: Role of the distance metric

“…In the last decade, path‐based reaction coordinates (RCs) have become an important tool for free‐energy calculations in complex molecular systems . The idea of sampling the system along some relevant path in a multidimensional space of predefined descriptors (like Cartesian coordinates of essential atoms or, in general, any collective variables [CVs]) helps to overcome the so‐called “curse of dimensionality”: the exponential scaling of the computational cost versus the number of descriptors used.…”