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Fluorinated Protein–Ligand Complexes: A Computational Perspective

L. Wehrhan, Bettina G. Keller – 2024

Fluorine is an element renowned for its unique properties. Its powerful capability to modulate molecular properties makes it an attractive substituent for protein binding ligands; however, the rational design of fluorination can be challenging with effects on interactions and binding energies being difficult to predict. In this Perspective, we highlight how computational methods help us to understand the role of fluorine in protein–ligand binding with a focus on molecular simulation. We underline the importance of an accurate force field, present fluoride channels as a showcase for biomolecular interactions with fluorine, and discuss fluorine specific interactions like the ability to form hydrogen bonds and interactions with aryl groups. We put special emphasis on the disruption of water networks and entropic effects.

Fluorinated Protein–Ligand Complexes: A Computational Perspective
L. Wehrhan, Bettina G. Keller
J. Phys. Chem. B 2024, 128, 5925−5934