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@article{1371195,
author = {Janoš, Pavel and Trnka, Tomáš and Kozmon, Stanislav and Tvaroška, Igor and Koča, Jaroslav},
article_location = {Washington},
article_number = {12},
doi = {http://dx.doi.org/10.1021/acs.jctc.6b00531},
keywords = {QM/MM; glycosyltransferase; reaction mechanism; enzyme; DFT; Ab Initio MD},
language = {eng},
issn = {1549-9618},
journal = {Journal of Chemical Theory and Computation},
title = {Different QM/MM Approaches To Elucidate Enzymatic Reactions: Case Study on ppGalNAcT2},
url = {http://dx.doi.org/10.1021/acs.jctc.6b00531},
volume = {12},
year = {2016}
}
TY - JOUR
ID - 1371195
AU - Janoš, Pavel - Trnka, Tomáš - Kozmon, Stanislav - Tvaroška, Igor - Koča, Jaroslav
PY - 2016
TI - Different QM/MM Approaches To Elucidate Enzymatic Reactions: Case Study on ppGalNAcT2
JF - Journal of Chemical Theory and Computation
VL - 12
IS - 12
SP - 6062-6076
EP - 6062-6076
PB - American Chemical Society
SN - 15499618
KW - QM/MM
KW - glycosyltransferase
KW - reaction mechanism
KW - enzyme
KW - DFT
KW - Ab Initio MD
UR - http://dx.doi.org/10.1021/acs.jctc.6b00531
L2 - http://dx.doi.org/10.1021/acs.jctc.6b00531
N2 - Hybrid QM/MM computational studies can provide invaluable insight into the mechanisms of enzymatic reactions that can be exploited for rational drug design. Various approaches are available for such studies. However, their strengths and weaknesses may not be immediately apparent. Using the retaining glycosyltransferase ppGalNAcT2 as a case study, we compare different methodologies used to obtain reaction paths and transition state information. Ab Initio MD using CPMD coupled with the String Method is used to derive the minimum free energy reaction path. The geometrical features of the free energy path, especially around the transition state, agree with the minimum potential energy path obtained by the much less computationally expensive Nudged Elastic Band method. The barrier energy, however, differs by 8 kcal/mol. The free energy surface generated by metadynamics provides a rough overview of the reaction and can confirm the physical relevance of optimized paths or provide an initial guess for path optimization methods. Calculations of enzymatic reactions are usually performed at best at the DFT level of theory. A comparison of widely used functionals with high-level DLPNO-CCSD(T)/CBS data on the potential energy profile serves as a validation of the usability of DFT for this type of enzymatic reaction. The M06-2X meta-hybrid functional in particular matches the DLPNO-CCSD(T)/CBS reference extremely well with errors within 1 kcal/mol. However, even pure-GGA functional OPBE provides sufficient accuracy for this type of study.
ER -
JANOŠ, Pavel, Tomáš TRNKA, Stanislav KOZMON, Igor TVAROŠKA a Jaroslav KOČA. Different QM/MM Approaches To Elucidate Enzymatic Reactions: Case Study on ppGalNAcT2. \textit{Journal of Chemical Theory and Computation}. Washington: American Chemical Society, 2016, roč.~12, č.~12, s.~6062-6076. ISSN~1549-9618. Dostupné z: https://dx.doi.org/10.1021/acs.jctc.6b00531.
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