posted on 2024-01-24, 19:45authored byChristopher
R. Travis, Kelsey M. Kean, Katherine I. Albanese, Hanne C. Henriksen, Joseph W. Treacy, Elaine Y. Chao, K. N. Houk, Marcey L. Waters
In the last 40 years, cation−π interactions
have become
part of the lexicon of noncovalent forces that drive protein binding.
Indeed, tetraalkylammoniums are universally bound by aromatic cages
in proteins, suggesting that cation−π interactions are
a privileged mechanism for binding these ligands. A prominent example
is the recognition of histone trimethyllysine (Kme3) by the conserved
aromatic cage of reader proteins, dictating gene expression. However,
two proteins have recently been suggested as possible exceptions to
the
conventional understanding of tetraalkylammonium recognition. To broadly
interrogate the role of cation−π interactions in protein
binding interactions, we report the first large-scale comparative
evaluation of reader proteins for a neutral Kme3 isostere, experimental
and computational mechanistic studies, and structural analysis. We
find unexpected widespread binding of readers to a neutral isostere
with the first examples of readers that bind the neutral isostere
more tightly than Kme3. We find that no single factor dictates the
charge selectivity, demonstrating the challenge of predicting such
interactions. Further, readers that bind both cationic and neutral
ligands differ in mechanism: binding Kme3 via cation−π
interactions and the neutral isostere through the hydrophobic effect
in the same aromatic cage. This discovery explains apparently contradictory
results in previous studies, challenges traditional understanding
of molecular recognition of tetraalkylammoniums by aromatic cages
in myriad protein–ligand interactions, and establishes a new
framework for selective inhibitor design by exploiting differences
in charge dependence.