Decoding dissociation pathways of ligands in prolyl oligopeptidase

Area of Science:

• Biochemistry
• Neuroscience
• Computational Biology

Background:

• Neurodegenerative diseases like Alzheimer’s and Parkinson’s represent a significant global health challenge.
• Prolyl oligopeptidase (PREP) is a potential therapeutic target due to its role in interacting with pathological proteins (e.g., α-synuclein, Tau) and influencing protein aggregation.
• Existing PREP inhibitors primarily target enzymatic activity, but new ligands (HUPs) modulate crucial protein-protein interactions (PPIs) involved in disease pathology.

Purpose of the Study:

• To investigate the binding pathways and stability of structurally diverse ligands targeting PREP.
• To understand how ligand structure influences binding mechanisms and interaction with PREP.
• To explore the potential of HUPs in disrupting non-enzymatic PPIs relevant to neurodegeneration.

Main Methods:

• Molecular dynamics simulations and enhanced sampling techniques were employed.
• The PLUMED module 'maze' was used to analyze ligand binding and unbinding pathways.
• Umbrella sampling was utilized to generate free-energy profiles and identify kinetic bottlenecks.

Main Results:

• Structurally different ligands exhibit distinct binding and unbinding pathways.
• Traditional inhibitors (e.g., KYP-2047) show preference for the central tunnel of PREP's β-propeller domain.
• HUP ligands, like HUP-55, display pathway hopping, exploring multiple binding regions before exiting, suggesting adaptability.
• Ligand binding dynamics and pathway selection are critical for PREP modulation.

Conclusions:

• Ligand dynamics and binding pathways are crucial for the mechanism of action of PREP inhibitors.
• HUPs' ability to interact with multiple sites and adapt to PREP conformational changes may underpin their PPI-targeting efficacy.
• Future drug design for PREP and related targets should consider both binding pathways and ligand dynamics for enhanced therapeutic outcomes.