A new appreciation for water networks
Armed with their new approach, the researchers conducted a systematic analysis showing the importance of water networks. Water, one of the most crucial and abundant molecules on Earth, plays an active role in the process of freezing conformations. This is particularly true at protein-ligand binding sites.
"This is the first time that we have systematically shown the importance of temperature on water networks for modulating the ligand binding interface, which is where biology happens," Fischer said. "Water is often ignored in the drug-discovery process, but we've shown that in addition to having a profound effect on ligand binding, water also influences binding site residues, capturing them in positions that differ depending on the temperature."
Flipper and the conformational barcode system that facilitates comparisons of different ligands at different temperatures is freely available to enable other researchers to identify such patterns in their own datasets.
Authors and funding
The study's other authors are Karlo Lopez, California State University; and Murugendra Vanarotti and Jayaraman Seetharaman of St. Jude.
The study was supported by grants from the National Institutes of Health (1R35GM142772-01, and P30GM133893), the Department of Energy Office of Biological and Environmental Research (KP1607011); an Academic Programs Special Fellowship, and ALSAC, the fundraising and awareness organization of St. Jude.
Read the full text of the Angewandte Chemie article:
Water networks repopulate protein-ligand interfaces with temperature
Angewandte Chemie, published June 1, 2022
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