Mechanism for the stabilization of protein clusters above the solubility curve: the role of non-ideal chemical reactions

TL;DR

This paper examines how non-ideal, state-dependent chemical reactions influence the stability of dense protein clusters, challenging previous models and suggesting that such reactions disrupt cluster stabilization mechanisms.

Contribution

The study revisits a prior DDFT model, incorporating state-dependent reaction rates to show their destabilizing effect on protein cluster stabilization.

Findings

State-dependent reaction rates disrupt cluster stability.

Inclusion of realistic physics corrects unphysical model assumptions.

Proposed stabilization mechanism fails under non-ideal reactions.

Abstract

Dense protein clusters are known to play an important role in nucleation of protein crystals from dilute solutions. While these have generally been thought to be formed from a metastable phase, the observation of similar, if not identical, clusters above the critical point for the dilute-solution/strong-solution phase transition has thrown this into doubt. Furthermore, the observed clusters are stable for relatively long times. Because protein aggregation plays an important role in some pathologies, understanding the nature of such clusters is an important problem. One mechanism for the stabilization of such structures was proposed by Pan, Vekilov and Lubchenko and was investigated using a DDFT model which confirmed the viability of the model. Here, we revisit that model and incorporate additional physics in the form of state-dependent reaction rates. We show by a combination of numerical results and general arguments that the state-dependent rates disrupt the stability mechanism. Finally, we argue that the state-depedent reactions correct unphysical aspects of the model with ideal (state-independent) reactions and that this necessarily leads to the failure of the proposed mechanism.