Enzymes are nature’s catalysts, reducing the timescales of the chemical reactions that make biology possible from millions of years to fractions of seconds (Warshel et al. 2006b; Wolfenden and Snider 2001). On the one hand, they are “merely” large molecules: polymers of amino acids folded into a particular three-dimensional (3-D) structure in order to solve specic chemical problems. However, despite their deceptive simplicity and over a century’s worth of extensive research e ort, the molecular basis for their tremendous catalytic prociencies remains highly controversial and, to some extent, poorly understood. Tying in with this, a large number of hypotheses have been put forward over the years in order to explain how enzymes really work (e.g., Benkovic et al. 2008; Hammes-Schi er 2013; Kamerlin and Warshel 2010a; Kamerlin, Mavri et al. 2010; Nagel and Klinman 2009; Villali and Kern 2010; Warshel et al. 2006b; Zalatan and Herschlag 2009).