Electronic Energy Migration in Protein Polymers Associated with Neurodegenerative Diseases

<jats:p>Neurodegenerative diseases are primarily characterized by the accumulation of misfolded protein aggregates in the brain. In addition to their pathological roles, these aggregates have been proposed to transduce photochemical stimuli into biochemical responses. The lattice-like structure of closely spaced aromatic residue chromophores in protein aggregates has raised the possibility of electronic energy migration over large distances, similar to photosynthetic light harvesting. Here, we investigate electronic energy migration in proteins associated with major neurodegenerative proteinopathies across three different states: monomers, fibrils, and extended polymeric assemblies using kinetic Monte Carlo simulations on structures extracted from the Protein Data Bank (PDB) to predict the distances over which electronic energy migration (characterized by the photoexcitation diffusion length; LD) can 2 take place in these structures. We find that repeated energy transfer ’hopping’ in the singlet state (through Förster resonance energy transfer; FRET) occurs over characteristic diffusion lengths of up to approximately 2.0 nm, with the longest values observed for the multiple system atrophy (MSA) associated α-synuclein structure (PDB 6XYO) in the polymeric state, whereas triplet state migration (through Dexter electron transfer; DET) is maximized in the fibrillar state (up to 0.85 nm) in the Alzheimer’s disease Aβ42 fibril structure (PDB 7Q4M) and is substantially reduced in polymers. We observe substantial variation in LD across monomeric, fibrillar, and polymeric states, indicating that the supramolecular organization strongly influences electronic energy migration. Because the calculated diffusion lengths are considerably smaller than the dimensions of protein assemblies, incoherent electronic energy migration is likely to remain localized within protein polymers associated with neurodegenerative diseases.</jats:p>