Here we present a modified version of the on-the-fly string method for the localization of the minimum free energy path in a space of arbitrary collective variables. In the proposed approach the shape of the biasing potential is controlled by only two force constants, defining the width of the potential along the string and orthogonal to it. The force constants and the distribution of the string nodes are optimized during the simulation, improving the convergence. The optimized parameters can be used for umbrella sampling with a path CV along the converged string as the reaction coordinate. We test the new method with three fundamentally different processes: chloride attack to chloromethane in bulk water, alanine dipeptide isomerization, and the enzymatic conversion of isochorismate to piruvate. In each case the same set of parameters resulted in a rapidly converging simulation and a precise estimation of the potential of mean force. Therefore, the default settings can be used for a wide range of processes, making the method essentially parameter free and more user-friendly.

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.

M.HhaI is a DNA Methyltransferase from Haemophilus haemolyticus that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the C 5 position of a cytosine. This enzyme is a paradigmatic model for C 5 DNA Methyltransferases due to its major homology to mammalian enzymes and to the availability of high resolution structures of the DNA-enzyme complex. In spite of the number of experimental and theoretical analysis carried out for this system many mechanistic details remain unraveled. We have used full atomistic classical Molecular Dynamics simulations to explore the protein-SAM-DNA ternary complex where the target cytosine base is flipped out into the active site for both the wild type and Glu119Gln mutant. The relaxed structure was used for a combined Quantum Mechanics/Molecular Mechanics exploration of the reaction mechanism using the string method. Exploration of multidimensional Free Energy Surfaces allowed determining a complete picture of the reaction mechanism in agreement with experimental observations. In our proposal

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