The interplay of intrinsic disorder and macromolecular crowding on {\alpha}-synuclein fibril formation

TL;DR

This study models how intrinsic disorder and macromolecular crowding influence {}-synuclein fibril formation, revealing crowding reduces conformational entropy and can induce fibril formation, providing insights into Parkinson's disease mechanisms.

Contribution

The paper introduces a lattice gas model that exactly incorporates crowding effects into {}-synuclein behavior, linking crowding to reduced entropy and fibril formation.

Findings

Crowding reduces the internal entropy of disordered {}-syn states.

The model shows crowding can induce fibril formation scenarios.

Macromolecular crowding may resolve controversies over {}-syn tetramers.

Abstract

{\alpha}-synuclein ({\alpha}-syn) is an intrinsically disordered protein which is considered to be one of the causes of Parkinson's disease. This protein forms amyloid fibrils when in a highly concentrated solution. The fibril formation of {\alpha}-syn is induced not only by increases in {\alpha}-syn concentration but also by macromolecular crowding. In order to investigate the coupled effect of the intrinsic disorder of {\alpha}-syn and macromolecular crowding, we construct a lattice gas model of {\alpha}-syn in contact with a crowding agent reservoir based on statistical mechanics. The main assumption is that {\alpha}-syn can be expressed as coarse-grained particles with internal states coupled with effective volume; and disordered states are modeled by larger particles with larger internal entropy than other states. Thanks to the simplicity of the model, we can exactly calculate the number of conformations of crowding agents, and this enables us to prove that the original grand canonical ensemble with a crowding agent reservoir is mathematically equivalent to a canonical ensemble without crowding agents. In this expression, the effect of macromolecular crowding is absorbed in the internal entropy of disordered states; it is clearly shown that the crowding effect reduces the internal entropy. Based on Monte Carlo simulation, we provide scenarios of crowding-induced fibril formation. We also discuss the recent controversy over the existence of helically folded tetramers of {\alpha}-syn, and suggest that macromolecular crowding is the key to resolving the controversy.