Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site

Gerlits, Oksana; Wymore, Troy; Das, Amit; Shen, Chen -Hsiang; Parks, Jerry M.; Smith, Jeremy C.; Weiss, Kevin L.; Keen, David A.; Blakeley, Matthew P.; Louis, John M.; Langan, Paul; Weber, Irene T.; Kovalevsky, Andrey

doi:10.1002/anie.201509989

Title: Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site

Journal Article · Wed Mar 09 00:00:00 EST 2016 · Angewandte Chemie (International Edition)

DOI:https://doi.org/10.1002/anie.201509989· OSTI ID:1255684

Gerlits, Oksana ^[1]; Wymore, Troy ^[1]; Das, Amit ^[2]; Shen, Chen -Hsiang ^[3]; Parks, Jerry M. ^[1]; Smith, Jeremy C. ^[1]; Weiss, Kevin L. ^[1]; Keen, David A. ^[4]; Blakeley, Matthew P. ^[5]; Louis, John M. ^[6]; Langan, Paul ^[1]; Weber, Irene T. ^[3]; Kovalevsky, Andrey ^[1]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
BARC, Mumbai (India)
Georgia State Univ., Atlanta, GA (United States)
Rutherford Appleton Lab., Didcot (United Kingdom)
Institut Laue Langevin, Grenoble Cedex (France)
National Institutes of Health, Bethesda, MD (United States)

Neutron crystallography was used to directly locate two protons before and after a pH-induced two-proton transfer between catalytic aspartic acid residues and the hydroxy group of the bound clinical drug darunavir, located in the catalytic site of enzyme HIV-1 protease. The two-proton transfer is triggered by electrostatic effects arising from protonation state changes of surface residues far from the active site. The mechanism and pH effect are supported by quantum mechanics/molecular mechanics (QM/MM) calculations. The low-pH proton configuration in the catalytic site is deemed critical for the catalytic action of this enzyme and may apply more generally to other aspartic proteases. Neutrons therefore represent a superb probe to obtain structural details for proton transfer reactions in biological systems at a truly atomic level.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1255684

Journal Information:: Angewandte Chemie (International Edition), Vol. 55, Issue 16; ISSN 1433-7851

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 38 works

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