David Baker lab preprint: de novo design of enzymes with allosteric on/off switches

DaveJuergens · x · 2026-09-16

A new preprint from the David Baker lab presents a general de novo strategy for compact enzymes whose catalytic activity can be switched on or off by a separately designed protein effector binding at a distal site. The core idea engineers an energy landscape with two nearby conformational states — an active state with optimal catalytic geometry and an inactive state with subtly distorted active sites — and the effector selectively stabilizes one. Methodologically, partial RFdiffusion (adding 1–3 Å Gaussian noise then denoising) generates alternative backbones close to the starting fold, enriching subtle functional conformations. A milestone toward controllable, rather than merely functional, designed enzymes.

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