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Title: Acid Catalysis in Basic Solution: A Supramolecular Host PromotesOrthoformate Hydrolysis

Abstract

Though many enzymes can promote chemical reactions by tuning substrate properties purely through the electrostatic environment of a docking cavity, this strategy has proven challenging to mimic in synthetic host-guest systems. Here we report a highly-charged, water soluble, metal-ligand assembly with a hydrophobic interior cavity that thermodynamically stabilizes protonated substrates and consequently catalyzes the normally acidic hydrolysis of orthoformates in basic solution, with rate accelerations of up to 890-fold. The catalysis reaction obeys Michaelis-Menten kinetics, exhibits competitive inhibition, and the substrate scope displays size selectivity consistent with the constrained binding environment of the molecular host. Synthetic chemists have long endeavored to design host molecules capable of selectively binding slow-reacting substrates and catalyzing their chemical reactions. While synthetic catalysts are often site-specific and require certain properties of the substrate to insure catalysis, enzymes are often able to modify basic properties of the bound substrate such as pK{sub a} in order to enhance reactivity. Two common motifs used by nature to activate otherwise unreactive compounds are the precise arrangement of hydrogen-bonding networks and electrostatic interactions between the substrate and adjacent residues of the protein. Precise arrangement of hydrogen bonding networks near the active sites of proteins can lead to well-tuned pK{sub a}-matching,more » and can result in pK{sub a} shifts of up to eight units, as shown in bacteriorhodopsin. Similarly, purely electrostatic interactions can greatly favor charged states and have been responsible for pK{sub a} shifts of up to five units for acetoacetate decarboxylase. Attempts have been made to isolate the contributions of electrostatic versus covalent interactions to such pK{sub a} shifts; however this remains a difficult challenge experimentally. This challenge emphasizes the importance of synthesizing host molecules that, like enzyme cavities, can enhance binding of small molecular guests and, in a few cases, catalyze chemical reactions. Supramolecular assemblies with available functional groups have been used to generate solution-state pK{sub a} shifts of up to two pK{sub a} units and to catalyze chemical reactions. Synthetic hosts often rely on hydrogen-bonding or ion-dipole interactions for guest inclusion, and numerous studies have investigated the effects of charge on guest binding affinities in supramolecular host-guest systems. We report here a synthetic supramolecular host assembly that relies exclusively on electrostatic and hydrophobic interactions for thermodynamic stabilization of protonated substrates. As nature has exploited pK{sub a} shifts to activate otherwise unreactive substrates toward catalysis, this stabilization is exploited to promote acid-catalyzed hydrolyses in strongly basic solution.« less

Authors:
; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director, Office of Science; National ScienceFoundation
OSTI Identifier:
923298
Report Number(s):
LBNL-63320
Journal ID: ISSN 0193-4511; SCEHDK; R&D Project: 402104; BnR: KC0302010; TRN: US200804%%1049
DOE Contract Number:  
DE-AC02-05CH11231; NSF:2004016723
Resource Type:
Journal Article
Journal Name:
Science
Additional Journal Information:
Journal Volume: 316; Journal Issue: 5821; Related Information: Journal Publication Date: 04/2007; Journal ID: ISSN 0193-4511
Country of Publication:
United States
Language:
English
Subject:
37; ACETOACETATES; BONDING; CATALYSIS; CATALYSTS; CAVITIES; CHEMICAL REACTIONS; DECARBOXYLASES; DESIGN; ELECTROSTATICS; ENZYMES; FUNCTIONALS; HYDROGEN; HYDROLYSIS; KINETICS; PROTEINS; RESIDUES; STABILIZATION; SUBSTRATES; THERMODYNAMICS; TUNING

Citation Formats

Pluth, Michael D, Bergman, Robert G, and Raymond, Kenneth N. Acid Catalysis in Basic Solution: A Supramolecular Host PromotesOrthoformate Hydrolysis. United States: N. p., 2007. Web. doi:10.1126/science.1138748.
Pluth, Michael D, Bergman, Robert G, & Raymond, Kenneth N. Acid Catalysis in Basic Solution: A Supramolecular Host PromotesOrthoformate Hydrolysis. United States. https://doi.org/10.1126/science.1138748
Pluth, Michael D, Bergman, Robert G, and Raymond, Kenneth N. Wed . "Acid Catalysis in Basic Solution: A Supramolecular Host PromotesOrthoformate Hydrolysis". United States. https://doi.org/10.1126/science.1138748. https://www.osti.gov/servlets/purl/923298.
@article{osti_923298,
title = {Acid Catalysis in Basic Solution: A Supramolecular Host PromotesOrthoformate Hydrolysis},
author = {Pluth, Michael D and Bergman, Robert G and Raymond, Kenneth N},
abstractNote = {Though many enzymes can promote chemical reactions by tuning substrate properties purely through the electrostatic environment of a docking cavity, this strategy has proven challenging to mimic in synthetic host-guest systems. Here we report a highly-charged, water soluble, metal-ligand assembly with a hydrophobic interior cavity that thermodynamically stabilizes protonated substrates and consequently catalyzes the normally acidic hydrolysis of orthoformates in basic solution, with rate accelerations of up to 890-fold. The catalysis reaction obeys Michaelis-Menten kinetics, exhibits competitive inhibition, and the substrate scope displays size selectivity consistent with the constrained binding environment of the molecular host. Synthetic chemists have long endeavored to design host molecules capable of selectively binding slow-reacting substrates and catalyzing their chemical reactions. While synthetic catalysts are often site-specific and require certain properties of the substrate to insure catalysis, enzymes are often able to modify basic properties of the bound substrate such as pK{sub a} in order to enhance reactivity. Two common motifs used by nature to activate otherwise unreactive compounds are the precise arrangement of hydrogen-bonding networks and electrostatic interactions between the substrate and adjacent residues of the protein. Precise arrangement of hydrogen bonding networks near the active sites of proteins can lead to well-tuned pK{sub a}-matching, and can result in pK{sub a} shifts of up to eight units, as shown in bacteriorhodopsin. Similarly, purely electrostatic interactions can greatly favor charged states and have been responsible for pK{sub a} shifts of up to five units for acetoacetate decarboxylase. Attempts have been made to isolate the contributions of electrostatic versus covalent interactions to such pK{sub a} shifts; however this remains a difficult challenge experimentally. This challenge emphasizes the importance of synthesizing host molecules that, like enzyme cavities, can enhance binding of small molecular guests and, in a few cases, catalyze chemical reactions. Supramolecular assemblies with available functional groups have been used to generate solution-state pK{sub a} shifts of up to two pK{sub a} units and to catalyze chemical reactions. Synthetic hosts often rely on hydrogen-bonding or ion-dipole interactions for guest inclusion, and numerous studies have investigated the effects of charge on guest binding affinities in supramolecular host-guest systems. We report here a synthetic supramolecular host assembly that relies exclusively on electrostatic and hydrophobic interactions for thermodynamic stabilization of protonated substrates. As nature has exploited pK{sub a} shifts to activate otherwise unreactive substrates toward catalysis, this stabilization is exploited to promote acid-catalyzed hydrolyses in strongly basic solution.},
doi = {10.1126/science.1138748},
url = {https://www.osti.gov/biblio/923298}, journal = {Science},
issn = {0193-4511},
number = 5821,
volume = 316,
place = {United States},
year = {2007},
month = {12}
}