The formation of protein aggregates is one of the leading causes of neuronal malfunction and subsequent brain damage in many neurodegenerative diseases. In Parkinson's disease, α-synucleins are involved in the accumulation of aggregates. The origin of aggregation is unknown, but there is convincing evidence that it can be reduced by prolyl oligopeptidase (PREP) inhibition. This effect cannot simply be related to the inhibition of the enzyme's catalytic function since not all PREP inhibitors stop α-synuclein aggregation. Finding differences in the dynamics of the enzyme inhibited by different compounds would allow us to identify the protein regions involved in the interaction between PREP and α-synuclein. Here, we investigate the effects of three PREP inhibitors, each of which affects α-synuclein aggregation to a different extent. We use molecular dynamics modelling to identify the molecular mechanisms underlying PREP inhibition and find structural differences between inhibitor-PREP systems. We suggest that even subtle variations in enzyme dynamics affect its interactions with α-synucleins. Our identification of these regions may therefore be biologically relevant in preventing α-synuclein aggregate formation.