Synchronous vs asynchronous chain motion in alpha-synuclein contact dynamics.

alpha-Synuclein (alpha-syn) is an intrinsically unstructured 140-residue neuronal protein of uncertain function that is implicated in the etiology of Parkinson's disease. Tertiary contact formation rate constants in alpha-syn, determined from diffusion-limited electron-transfer kinetics measurements, are poorly approximated by simple random polymer theory. One source of the discrepancy between theory and experiment may be that interior-loop formation rates are not well approximated by end-to-end contact dynamics models. We have addressed this issue with Monte Carlo simulations to model asynchronous and synchronous motion of contacting sites in a random polymer. These simulations suggest that a dynamical drag effect may slow interior-loop formation rates by about a factor of 2 in comparison to end-to-end loops of comparable size. The additional deviations from random coil behavior in alpha-syn likely arise from clustering of hydrophobic residues in the disordered polypeptide.