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@article{1503342,
author = {Beerens, Koen and Mazurenko, Stanislav and Kunka, Antonín and Marques, Sérgio Manuel and Hansen, N. and Musil, Miloš and Chaloupková, Radka and Waterman, Jitka and Brezovský, Jan and Bednář, David and Prokop, Zbyněk and Damborský, Jiří},
article_location = {WASHINGTON},
article_number = {10},
doi = {http://dx.doi.org/10.1021/acscatal.8b01677},
keywords = {protein stabilization; thermostability; evolutionary analysis; force-field calculations; computational tools; entropy; enthalpy; thermodynamic integration},
language = {eng},
issn = {2155-5435},
journal = {ACS Catalysis},
title = {Evolutionary Analysis As a Powerful Complement to Energy Calculations for Protein Stabilization},
url = {https://loschmidt.chemi.muni.cz/peg/category/publications/#2018},
volume = {8},
year = {2018}
}
TY - JOUR
ID - 1503342
AU - Beerens, Koen - Mazurenko, Stanislav - Kunka, Antonín - Marques, Sérgio Manuel - Hansen, N. - Musil, Miloš - Chaloupková, Radka - Waterman, Jitka - Brezovský, Jan - Bednář, David - Prokop, Zbyněk - Damborský, Jiří
PY - 2018
TI - Evolutionary Analysis As a Powerful Complement to Energy Calculations for Protein Stabilization
JF - ACS Catalysis
VL - 8
IS - 10
SP - 9420-9428
EP - 9420-9428
PB - AMER CHEMICAL SOC
SN - 21555435
KW - protein stabilization
KW - thermostability
KW - evolutionary analysis
KW - force-field calculations
KW - computational tools
KW - entropy
KW - enthalpy
KW - thermodynamic integration
UR - https://loschmidt.chemi.muni.cz/peg/category/publications/#2018
N2 - Stability is one of the most important characteristics of proteins employed as biocatalysts, biotherapeutics, and biomaterials, and the role of computational approaches in modifying protein stability is rapidly expanding. We have recently identified stabilizing mutations in haloalkane dehalogenase DhaA using phylogenetic analysis but were not able to reproduce the effects of these mutations using force-field calculations. Here we tested four different hypotheses to explain the molecular basis of stabilization using structural, biochemical, biophysical, and computational analyses. We demonstrate that stabilization of DhaA by the mutations identified using the phylogenetic analysis is driven by both entropy and enthalpy contributions, in contrast to primarily enthalpy-driven stabilization by mutations designed by the force-field Comprehensive bioinformatics analysis revealed that more than half (53%) of 1 099 evolution-based stabilizing mutations would be evaluated as destabilizing by force-field calculations. Thermodynamic integration considers both folded and unfolded states and can describe the entropic component of stabilization, yet it is not suitable for predictive purposes due to its high computational demands. Altogether, our results strongly suggest that energetic calculations should be complemented by a phylogenetic analysis in protein-stabilization endeavors.
ER -
BEERENS, Koen, Stanislav MAZURENKO, Antonín KUNKA, Sérgio Manuel MARQUES, N. HANSEN, Miloš MUSIL, Radka CHALOUPKOVÁ, Jitka WATERMAN, Jan BREZOVSKÝ, David BEDNÁŘ, Zbyněk PROKOP and Jiří DAMBORSKÝ. Evolutionary Analysis As a Powerful Complement to Energy Calculations for Protein Stabilization. \textit{ACS Catalysis}. WASHINGTON: AMER CHEMICAL SOC, 2018, vol.~8, No~10, p.~9420-9428. ISSN~2155-5435. Available from: https://dx.doi.org/10.1021/acscatal.8b01677.
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