Confinement Effects on the Kinetics and Thermodynamics of Protein Dimerization

TL;DR

This study investigates how cellular confinement influences the kinetics and thermodynamics of protein dimerization, revealing optimal and contrasting behaviors for free and tethered monomers through simulations and theoretical analysis.

Contribution

It introduces a combined simulation and theoretical framework to analyze confinement effects on protein dimerization, highlighting the optimal concentration for maximal rate and contrasting behaviors for tethered proteins.

Findings

Maximal dimerization rate at cellular concentration (~1mM).

Tethered chains show a plateau then decrease in rate with increasing concentration.

Simulation results align with experimental data.

Abstract

In the cell, protein complexes form relying on specific interactions between their monomers. Excluded volume effects due to molecular crowding would lead to correlations between molecules even without specific interactions. What is the interplay of these effects in the crowded cellular environment? We study dimerization of a model homodimer both when the mondimers are free or tethered to each other. We consider a structured environment: Two monomers first diffuse into a cavity of size $L$ and then fold and bind within the cavity. The folding and binding are simulated using molecular dynamics based on a simplified topology based model. The {\it confinement} in the cell is described by an effective molecular concentration $C \sim L^{-3}$. A two-state coupled folding and binding behavior is found. We show the maximal rate of dimerization occurred at an effective molecular concentration $C^{op}\simeq 1m$M which is a relevant cellular concentration. In contrast, for tethered chains the rate keeps at a plateau when $C<C^{op}$ but then decreases sharply when $C>C^{op}$. For both the free and tethered cases, the simulated variation of the rate of dimerization and thermodynamic stability with effective molecular concentration agrees well with experimental observations. In addition, a theoretical argument for the effects of confinement on dimerization is also made.