Allostery and Kinetic Proofreading

Kinetic proofreading is an error correction mechanism
present in
the processes of the central dogma and beyond and typically requires
the free energy of nucleotide hydrolysis for its operation. Though
the molecular players of many biological proofreading schemes are
known, our understanding of how energy consumption is managed to promote
fidelity remains incomplete. In our work, we introduce an alternative
conceptual scheme called “the piston model of proofreading”
in which enzyme activation through hydrolysis is replaced with allosteric
activation achieved through mechanical work performed by a piston
on regulatory ligands. Inspired by Feynman’s ratchet and pawl
mechanism, we consider a mechanical engine designed to drive the piston
actions powered by a lowering weight, whose function is analogous
to that of ATP synthase in cells. Thanks to its mechanical design,
the piston model allows us to tune the “knobs” of the
driving engine and probe the graded changes and trade-offs between
speed, fidelity, and energy dissipation. It provides an intuitive
explanation of the conditions necessary for optimal proofreading and
reveals the unexpected capability of allosteric molecules to beat
the Hopfield limit of fidelity by leveraging the diversity of states
available to them. The framework that we have built for the piston
model can also serve as a basis for additional studies of driven biochemical
systems.