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WIREs Comput Mol Sci
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Reaction coordinates and transition states in enzymatic catalysis

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Enzymatic reactions are complex chemical processes taking place in complex dynamic environments. Theoretical characterization of these reactions requires the determination of the reaction coordinate and the transition state ensemble. This is not an easy task because many degrees of freedom may be involved in principle. We present recent efforts to find good enzymatic reaction coordinates and the implications of these findings in the interpretation of enzymatic efficiency. In particular, we analyze different strategies based on the use of minimum free energy paths and direct localization of the dividing surface on multidimensional free energy surfaces. Another strategy is based on the generation of reactive trajectories, using the transition path sampling method, from which transition state configurations can be harvested. Most of the applications carried out until now coincide to stress the change in the nature of the reaction coordinate, in terms of the participation of the chemical and environmental degrees of freedom, as the reaction advances. The degrees of freedom of the chemical system are dominant at the transition state while environmental participation can be more important at early or late stages of the process.

Different surfaces have different number of recrossings: (a) no recrossings; (b) with recrossings.
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Cel7A reaction mechanism. Green lines and arrows indicate those coordinates participating in the reaction coordinate (RC).
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Interconversion between lactate and pyruvate catalyzed by human heart lactate dehydrogenase (LDH).
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Generation of reactive trajectories in transition path sampling.
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Committor distributions obtained for the isochorismate pyruvate lyase (IPL)‐catalyzed reaction using different strategies (a) Path CV/Euclidean metric; (b) Path CV/Correct metric; (c) GHTS.
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Isochorismate pyruvate lyase (IPL) reaction mechanism and collective variables (CVs) used (distances and the hybridization coordinates).
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General definition of a path collective variable (CV).
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The string method. String nodes are iteratively moved in the direction of lower free energy. After each iteration, the nodes are redistributed evenly along the string.
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Minimum free energy path (MFEP) on a two‐dimensional free energy surface (FES).
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Reaction catalyzed by dihydroalkane dehalogenase (DhlA).
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Committor distribution for different choices of reaction coordinate (RC) and transition state (TS). ρ is the probability density of committor values obtained for TS configurations: (a) perfect TS; (b) good RC, good TS; (c) good RC, bad TS; (d) bad RC.
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Software > Simulation Methods
Simulation Methods > Free Energy Methods
Structure and Mechanism > Computational Biochemistry and Biophysics

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