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

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

doi:10.1002/anie.201509989

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

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

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41 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	4924-4927
Number of pages	4
Journal	Angewandte Chemie - International Edition
Volume	55
Issue number	16
DOIs	https://doi.org/10.1002/anie.201509989
State	Published - Apr 11 2016

Funding

We thank the Center for Structural Molecular Biology (CSMB) at BES Scientific User Facilities Division, supported by the DOE Office of Biological and Environmental Research (BER), for facility use. O.G., P.L., and A.K. were partly supported by the DOE Office of Basic Energy Sciences (BES). K.L.W. was partly supported by CSMB. I.T.W. was partly supported by an NIH grant R01GM02920. The authors thank Institut Laue Langevin (beamline LADI-III) and Oak Ridge National Laboratory (IMAGINE beamline) for neutron beam time.

Funders	Funder number
Center for Structural Molecular Biology
DOE Office of Basic Energy Sciences
DOE Office of Biological and Environmental Research
Institut Laue Langevin
National Institutes of Health	R01GM02920
National Institute of General Medical Sciences	R01GM062920
Basic Energy Sciences
Biological and Environmental Research
Oak Ridge National Laboratory

Keywords

QM/MM modeling
aspartic protease
enzymes
neutron crystallography
proton transfer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.201509989

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Gerlits, O., Wymore, T., Das, A., Shen, C. H., Parks, J. M., Smith, J. C., Weiss, K. L., Keen, D. A., Blakeley, M. P., Louis, J. M., Langan, P., Weber, I. T., & Kovalevsky, A. (2016). Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site. Angewandte Chemie - International Edition, 55(16), 4924-4927. https://doi.org/10.1002/anie.201509989

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abstract = "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.",

keywords = "QM/MM modeling, aspartic protease, enzymes, neutron crystallography, proton transfer",

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

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doi = "10.1002/anie.201509989",

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Gerlits, O, Wymore, T, Das, A, Shen, CH, Parks, JM, Smith, JC, Weiss, KL, Keen, DA, Blakeley, MP, Louis, JM, Langan, P, Weber, IT & Kovalevsky, A 2016, 'Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site', Angewandte Chemie - International Edition, vol. 55, no. 16, pp. 4924-4927. https://doi.org/10.1002/anie.201509989

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T1 - Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site

AU - Gerlits, Oksana

AU - Wymore, Troy

AU - Das, Amit

AU - Shen, Chen Hsiang

AU - Parks, Jerry M.

AU - Smith, Jeremy C.

AU - Weiss, Kevin L.

AU - Keen, David A.

AU - Blakeley, Matthew P.

AU - Louis, John M.

AU - Langan, Paul

AU - Weber, Irene T.

AU - Kovalevsky, Andrey

PY - 2016/4/11

Y1 - 2016/4/11

N2 - 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.

AB - 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.

KW - QM/MM modeling

KW - aspartic protease

KW - enzymes

KW - neutron crystallography

KW - proton transfer

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

Abstract

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Keywords

UN SDGs

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