Proofreading through spatial gradients

TL;DR

This paper proposes a novel spatial gradient-based error correction mechanism in enzymatic processes, which enhances specificity without requiring traditional structural features, and explores how spatial tuning affects fidelity, speed, and energy use.

Contribution

It introduces a new spatial gradient-based proofreading mechanism that is more adaptable and easier to implement than traditional structural methods.

Findings

Spatial gradients can be used to achieve error correction in enzymes.

Tuning gradient length scales affects fidelity, speed, and energy dissipation.

Performance is limited by realistic diffusion and reaction rates.

Abstract

Key enzymatic processes in biology use the nonequilibrium error correction mechanism called kinetic proofreading to enhance their specificity. Kinetic proofreading typically requires several dedicated structural features in the enzyme, such as a nucleotide hydrolysis site and multiple enzyme-substrate conformations that delay product formation. Such requirements limit the applicability and the adaptability of traditional proofreading schemes. Here, we explore an alternative conceptual mechanism of error correction that achieves delays between substrate binding and subsequent product formation by having these events occur at distinct physical locations. The time taken by the enzyme-substrate complex to diffuse from one location to another is leveraged to discard wrong substrates. This mechanism does not require dedicated structural elements on the enzyme, making it easier to overlook in experiments but also making proofreading tunable on the fly. We discuss how tuning the length scales of enzyme or substrate concentration gradients changes the fidelity, speed and energy dissipation, and quantify the performance limitations imposed by realistic diffusion and reaction rates in the cell. Our work broadens the applicability of kinetic proofreading, and sets the stage for the study of spatial gradients as a possible route to specificity.