Iterative Annealing Mechanism for Protein and RNA Chaperones

TL;DR

This paper presents a unified theoretical framework called the iterative annealing mechanism (IAM) to explain how protein and RNA chaperones assist in folding complex biomolecules, optimizing their activity for biological efficiency.

Contribution

The study introduces the IAM as a universal model for understanding chaperone activity, revealing how these machines maximize folding yield within biological timescales.

Findings

Chaperones operate via an iterative annealing process.

Optimal RNA chaperone activity maximizes pre-RNA splicing yield.

Theoretical predictions align with biological efficiency constraints.

Abstract

Molecular chaperones are machines that consume copious amount of ATP to drive misfolded proteins or RNA to fold into functionally competent native states. Because the folding landscapes of biomolecules with complex native state topology are rugged consisting of multiple minima that are separated by large free energy barriers, folding occurs by the kinetic partitioning mechanism according to which only a small fraction of the molecules reach the folded state in biologically viable times. The rescue of such proteins and RNA require chaperones. Although the protein and RNA chaperones are profoundly different in their structure and action, the principles underlying their activity to produce the folded structures can be understood using a unified theoretical framework based on iterative annealing mechanism (IAM). Our theory shows that both these machines have evolved to the maximize the production of the steady state yield on biological times. Strikingly, theory predicts that only at a moderate level of RNA chaperone activity is the yield of the self-splicing pre-RNA is maximized in \textit{in vivo}.