View of the active site and Met20 loop corresponding to the closed state depicting atoms involved in the hydride transfer reaction. (b) The two-dimensional free energy surface along the ΔDrmsd order parameter versus hydride transfer distance between the atom N5 of DHF and C4 of NADPH. In the closed state (ΔDrmsd ≈ −3.5 Å), the distance between the cofactor and substrate fluctuates in the range of 3–4 Å, suitable for promotion of the hydride transfer reaction. (Fig. 3 of Arora K and Brooks, C. L. (2009), J. Amer. Chem. Soc. 131:5642, Copyright © 2007, The American Chemical Society)