The energetic landscape of CH–π interactions in protein–carbohydrate binding
Name
d4sc06246a.pdf
Description
Published version
Size
2.45 MB
Format
Adobe PDF
Checksum (MD5)
224c2b56dc1feb2963ffc685fc9d4a54
Author(s)
Keys, Allison M
Kastner, David W
Kiessling, Laura L
Kulik, Heather J
Date Issued
December 3, 2024
Journal
Chemical Science
Publisher
Royal Society of Chemistry
Citation
Chem. Sci., 2025,16, 1746-1761
Version
Final published version
Abstract
CH–π interactions between carbohydrates and aromatic amino acids play an essential role in biological systems that span all domains of life. Quantifying the strength and importance of these CH–π interactions is challenging because these interactions involve several atoms and can exist in many distinct orientations. To identify an orientational landscape of CH–π interactions, we constructed a dataset of close contacts formed between β-D-galactose residues and the aromatic amino acids, tryptophan, tyrosine, and phenylalanine, across crystallographic structures deposited in the Protein Data Bank. We carried out quantum mechanical calculations to quantify their interaction strengths. The data indicate that tryptophan-containing CH–π interactions have more favorable interaction energies than those formed by tyrosine or phenylalanine. The energetic differences between these amino acids are caused by the aromatic ring system electronics and size. We use individual distance and angle features to train random forest models to successfully predict the first-principles computed energetics of CH–π interactions. Using insights from our models, we define a tradeoff in CH–π interaction strength arising from the proximity of galactose carbons 1 and 2 versus carbons 4 and 6 to the aromatic amino acid. Our work demonstrates that a feature of CH–π stacking interactions is that numerous orientations allow for highly favorable interaction strengths.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Biological Engineering
Broad Institute of MIT and Harvard
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1039/d4sc06246a
