I’m sure many of us have come across instances where introduction of a single methyl group results in an unexpected increase in affinity. If you have you might like this paper in J Med Chem.

Methyl Effects on Protein–Ligand Binding

Cheryl S. Leung, Siegfried S. F. Leung, Julian Tirado-Rives, and William L. Jorgensen
A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event….The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.

DOI: 10.1021/jm3003697