A Two-Step Biopolymer Nucleation Model Shows a Nonequilibrium Critical Point

TL;DR

This paper introduces a novel two-step biopolymer nucleation model that explicitly incorporates assembly and conformational conversion dynamics, revealing a nonequilibrium critical point affecting intermediate stability and biological toxicity.

Contribution

It presents the first comprehensive model of two-step biopolymer nucleation that accounts for simultaneous assembly and conformational conversion dynamics.

Findings

Identification of a nonequilibrium critical point separating unstable and stable intermediate regimes.

Development of an experimentally motivated initiation-propagation mechanism for conformational conversion.

Quantitative predictions of intermediate concentration and composition in biopolymer nucleation.

Abstract

Biopolymer self-assembly pathways are central to biological activity, but are complicated by the ability of the monomeric subunits of biopolymers to adopt different conformational states. As a result, biopolymer nucleation often involves a two-step mechanism where the monomers first condense to form a metastable intermediate, and this then converts to a stable polymer by conformational rearrangement of its constituent monomers. While existing mathematical models neglect the dynamics by which intermediates convert to stable polymers, experiments and simulations show that these dynamics frequently occur on comparable timescales to condensation of intermediates and growth of mature polymers, and thus cannot be ignored. Moreover, nucleation intermediates are responsible for cell toxicity in pathologies such as Alzheimer's, Parkinson's, and prion diseases. Due to the relationship between conformation and biological function, the slow conversion dynamics of these species will strongly affect their toxicity. In this study, we present a modified Oosawa model which explicitly accounts for simultaneous assembly and conversion. To describe the conversion dynamics, we propose an experimentally motivated initiation-propagation (IP) mechanism in which the stable phase arises locally within the intermediate, and then spreads through additional conversion events induced by nearest-neighbor interactions, analogous to one-dimensional Glauber dynamics. Our mathematical analysis shows that the competing timescales of assembly and conversion result in a nonequilibrium critical point, separating a regime where intermediates are kinetically unstable from one where conformationally mixed intermediates can accumulate. Our work provides the first general model of two-step biopolymer nucleation, which can be used to quantitatively predict the concentration and composition of biologically crucial intermediates.