Mechanistic rules for de novo design of enzymes

TL;DR

This paper introduces a thermodynamically consistent model for enzyme operation, revealing how non-equilibrium conformational changes driven by energy from reactions can enable enzyme function, aiding de novo enzyme design.

Contribution

It presents a novel mechanistic model that explains enzyme function through bifurcations and dissipative coupling, complementing machine learning methods for enzyme design.

Findings

Enzymatic function can emerge via bifurcation in the model.

Non-equilibrium conformational changes drive catalysis.

Model supports de novo enzyme design strategies.

Abstract

Enzymes are nano-scale machines that have evolved to drive chemical reactions out of equilibrium in the right place at the right time. Given the complexity and specificity of enzymatic function, bottom-up design of enzymes presents a daunting task that is far more challenging than making passive molecules with specific binding affinities or building nano-scale mechanically active devices. We present a thermodynamically-consistent model for the operation of such a fuelled enzyme, which uses the energy from a favourable reaction to undergo non-equilibrium conformational changes that in turn catalyze a chemical reaction on an attached substrate molecule. We show that enzymatic function can emerge through a bifurcation upon appropriate implementation of momentum conservation on the effective reaction coordinates of the low dimensional description of the enzyme, and thanks to a generically present dissipative coupling. Our results can complement the recently developed strategies for de novo enzyme design based on machine learning approaches.