{\alpha}-synuclein ({\alpha}-syn) is the 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. We focused on the relation between the intrinsic disorder of {\alpha}-syn and macromolecular crowding, and constructed a simplified model of {\alpha}-syn including crowding agents based on statistical mechanics. The main assumption was that {\alpha}-syn can be expressed as coarse-grained particles with internal states coupled with effective volume; and disordered states were modeled by larger particles with larger internal entropy than other states. It was found that the crowding effect is taken into account as the effective internal entropy; and the crowding effect reduces the effective internal entropy of disordered states. From a 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.
{\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. We focused on the relation between the intrinsic disorder of {\alpha}-syn and macromolecular crowding, and constructed a lattice gas model of {\alpha}-syn including crowding agents based on statistical mechanics. The main assumption was that {\alpha}-syn can be expressed as coarse-grained particles with internal states coupled with effective volume; and disordered states were modeled by larger particles with larger internal entropy than other states. It was found that the crowding effect is taken into account as the effective internal entropy; and the crowding effect reduces the effective internal entropy of disordered states. 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.
R
the
an
R
simplified
lattice gas
R
From a
Based on