posted on 2016-10-27, 00:00authored byPavel Janoš, Tomáš Trnka, Stanislav Kozmon, Igor Tvaroška, Jaroslav Koča
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.