Low-barrier hydrogen bonds in enzyme cooperativity

Shaobo Dai, Lisa-Marie Funk, Fabian Rabe Pappenheim, Viktor Sautner, Mirko Paulikat, Benjamin Schröder, Jon Uranga, Ricardo A. Mata () and Kai Tittmann ()
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Shaobo Dai: Georg-August University Göttingen
Lisa-Marie Funk: Georg-August University Göttingen
Fabian Rabe Pappenheim: Georg-August University Göttingen
Viktor Sautner: Georg-August University Göttingen
Mirko Paulikat: Georg-August University Göttingen
Benjamin Schröder: Georg-August University Göttingen
Jon Uranga: Georg-August University Göttingen
Ricardo A. Mata: Georg-August University Göttingen
Kai Tittmann: Georg-August University Göttingen

Nature, 2019, vol. 573, issue 7775, 609-613

Abstract: Abstract The underlying molecular mechanisms of cooperativity and allosteric regulation are well understood for many proteins, with haemoglobin and aspartate transcarbamoylase serving as prototypical examples1,2. The binding of effectors typically causes a structural transition of the protein that is propagated through signalling pathways to remote sites and involves marked changes on the tertiary and sometimes even the quaternary level1–5. However, the origin of these signals and the molecular mechanism of long-range signalling at an atomic level remain unclear5–8. The different spatial scales and timescales in signalling pathways render experimental observation challenging; in particular, the positions and movement of mobile protons cannot be visualized by current methods of structural analysis. Here we report the experimental observation of fluctuating low-barrier hydrogen bonds as switching elements in cooperativity pathways of multimeric enzymes. We have observed these low-barrier hydrogen bonds in ultra-high-resolution X-ray crystallographic structures of two multimeric enzymes, and have validated their assignment using computational calculations. Catalytic events at the active sites switch between low-barrier hydrogen bonds and ordinary hydrogen bonds in a circuit that consists of acidic side chains and water molecules, transmitting a signal through the collective repositioning of protons by behaving as an atomistic Newton’s cradle. The resulting communication synchronizes catalysis in the oligomer. Our studies provide several lines of evidence and a working model for not only the existence of low-barrier hydrogen bonds in proteins, but also a connection to enzyme cooperativity. This finding suggests new principles of drug and enzyme design, in which sequences of residues can be purposefully included to enable long-range communication and thus the regulation of engineered biomolecules.

Date: 2019
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DOI: 10.1038/s41586-019-1581-9

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