期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 55, 期 16, 页码 4924-4927出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201509989
关键词
aspartic protease; enzymes; neutron crystallography; proton transfer; QM; MM modeling
资金
- DOE Office of Biological and Environmental Research (BER)
- DOE Office of Basic Energy Sciences (BES)
- CSMB
- NIH [R01GM02920]
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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