Enzyme Reaction Dynamics From Adaptive Reaction Coordinate Forces

Simulating enzyme reactions requires rigorous sampling of the protein frame, conformational space of the substrate and an accurate treatment of the electron dynamics. A flat histogram sampling method that adapts forces derived from the reaction coordinates and applied to reacting atoms in response to historical sampling is presented. The unconstrained steering of substrates away from equilibrium low energy wells, across high energy activation barriers toward product wells is demonstrated. FEARCF is packaged in a library and uses graph theory to define reaction coordinates. The method’s versatility is illustrated using QM/MM dynamics that show how TcTS straddles elimination and displacement mechanisms.