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Long‐Range Electrostatics‐Induced Two‐Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site
Author(s) -
Gerlits Oksana,
Wymore Troy,
Das Amit,
Shen ChenHsiang,
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
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201509989
Subject(s) - protonation , chemistry , proton , active site , catalysis , enzyme catalysis , electrostatics , computational chemistry , chemical physics , crystallography , stereochemistry , organic chemistry , physics , nuclear physics , ion
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.