We review molecular dynamic (MD) simulations of catalytic cycles for two typical cytochrome P450 enzymes that oxidize organic molecules (substrates). The simulations show that P450 is an open nanomachine that exchanges molecules with the outside and functions automatically once a substrate enters the enzyme’s cavity. The rest is done by reducing partners, a few residues, and water molecules that provide timed cues for these nanomachines. Fascinating outcomes are achieved, like opening/closing of the enzyme to uptake substrates, closings/openings of water gates to shuttle protons, and gating of channels through which the oxidized products exit and provide a ‘restart’ cue. The more we analyzed the MD trajectories, the more apparent it became: the amazing features of these enzymes are rooted in the chemistry of weak interactions in tight spaces. These cues are sensed by the protein and elicit the seemingly automatic cycle that governs the regio- and enantioselectivity of the enzymes.