Protein Folding: From Classical Issues to a New Perspective

TL;DR

This paper offers a new perspective on the protein folding problem, addressing the Levinthal paradox by combining theoretical insights and analysis of mutation effects, suggesting proteins fold within seconds rather than billions of years.

Contribution

It introduces a novel analytic approach to protein folding, proposing that proteins reach their native state rapidly and that mutations affect folding times but not the fundamental physical limits.

Findings

Proteins reach native state in seconds, not billions of years.

Mutations impact folding times but not the physical upper bound.

A new perspective may help solve the longstanding Anfinsen challenge.

Abstract

The Levinthal paradox exposes many critical questions on the protein folding problem, among which we could point out why proteins can reach their native state in a biologically reasonable time. A proper answer to this question is of foremost importance for evolutive biology since it enables us to understand life as we know it. Preliminary results, based on the upper bound protein marginal-stability limit, together with transition state theory arguments, lead us to show that two-state proteins must reach their native state in, at most, seconds rather than ($\sim 10^{27}$) years -- as indicated by a naive solution of the Levinthal paradox. This outcome -- added to the amide hydrogen-exchange protection factors analysis -- makes it possible for us to suggest how a protein point mutations and/or post-translational modifications impact its folding time scales but not its upper bound limit that obeys the physics ruling the process. Noteworthy for almost 50 years, the protein folding problem --mas the Levinthal paradox -- has been a topic of passionate debate because Anfinsen's challenge -- how a sequence encodes its folding -- remains unsolved despite the smashing success of accurately predicting the protein tridimensional structures by state-of-the-art numerical-methods. Aimed to unlock this long-standing challenge, we propose a new perspective of protein folding, specifically, as a problem that should be devised as an 'analytic whole' -- a Leibniz & Kant's notion. This viewpoint might help us decode Anfinsen's challenge and, thus, open new avenues for future research in the protein folding field.