CH⋅⋅⋅π Interactions between methyl and carbonyl groups in proteins: a small molecule check.

Derek Lowe highlights a recent article[1] postulating CH⋅⋅⋅π interactions in proteins. Here I report a quick check using the small molecule crystal structure database (CSD).

The search query (DOI: 10.14469/hpc/2594) is shown below.

1. The distance refers to that between the (normalised) position of a hydrogen on a 4-coordinated carbon atom and the centroid of a carbonyl group substituted with R=C or H. 
2. The angle is that subtended at the centroid. An approach orthogonal to the axis of the carbonyl group will have a value of 1.0 for the sine.
3. The torsion relates to the angle between the H…centroid and C-R vectors. The absolute value is constrained to 70-110° to filter only approaches towards the π-system of the carbonyl.
4. The search is further restricted to no disorder, no errors and R < 0.05. 

The two most interesting hits, both revealing short distances and ~orthogonal approaches to the π-system are:

• HIKWEF 10.5517/cc11m594, 2.045Å
• YAKNIB 10.5517/ccxkyx9, 2.274Å

Remember however that such “outliers” must always be carefully inspected. There are more numerous interactions in the region 2.4-2.6Å with a sine(angle) of >0.9 and and a close orthogonal approach to the π-system (green dots) which probably qualify for the title above. There seem many interesting but still putative small-molecule candidates for this proposed interaction postulated for proteins. 

Postscript:  Here the results of the search above with R= any of H,C,N,O,F,Cl up to values of the distance <2.4Å, which show a range of interesting (green) points.

References

1. F.A. Perras, D. Marion, J. Boisbouvier, D.L. Bryce, and M.J. Plevin, "Observation of CH⋅⋅⋅π Interactions between Methyl and Carbonyl Groups in Proteins", Angewandte Chemie International Edition, vol. 56, pp. 7564-7567, 2017. http://dx.doi.org/10.1002/anie.201702626