Unveiling prolyl oligopeptidase ligand migration by comprehensive computational techniques.

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Prolyl oligopeptidase (POP) is a key pharmaceutical target due to its role in cleaving oligopeptides.
• Understanding ligand migration pathways in POP is crucial but challenging due to its size and buried active site.

Purpose of the Study:

• To exhaustively sample ligand and substrate interactions with POP.
• To elucidate the entrance and exit pathways of ligands and products within POP.

Main Methods:

• Utilized protein energy landscape exploration with over 3000 molecular dynamics trajectories.
• Simulated binding and migration of the inhibitor Z-pro-prolinal.
• Modeled substrate binding, cleavage, and product release of an undecapeptide.

Main Results:

• Z-pro-prolinal explored all accessible surface areas, entering through the β-propeller domain pore.
• Identified multiple ligand entrance points into POP's internal cavity.
• Observed nonbiased product (dipeptide) exit via a flexible loop, distinct from the entrance site.

Conclusions:

• Ligand and product transport in POP involves distinct entrance and exit mechanisms.
• Advanced sampling techniques are effective for studying large, complex enzymes like POP.
• Findings provide a mechanistic basis for POP inhibitor design and drug development.