Journal of Molecular Modeling

, Volume 18, Issue 1, pp 145–150

Brønsted-Evans-Polanyi relationships for C–C bond forming and C–C bond breaking reactions in thiamine-catalyzed decarboxylation of 2-keto acids using density functional theory

  • Rajeev Surendran Assary
  • Linda J. Broadbelt
  • Larry A. Curtiss
Original Paper

DOI: 10.1007/s00894-011-1062-z

Cite this article as:
Assary, R.S., Broadbelt, L.J. & Curtiss, L.A. J Mol Model (2012) 18: 145. doi:10.1007/s00894-011-1062-z


The concept of generalized enzyme reactions suggests that a wide variety of substrates can undergo enzymatic transformations, including those whose biotransformation has not yet been realized. The use of quantum chemistry to evaluate kinetic feasibility is an attractive approach to identify enzymes for the proposed transformation. However, the sheer number of novel transformations that can be generated makes this impractical as a screening approach. Therefore, it is essential to develop structure/activity relationships based on quantities that are more efficient to calculate. In this work, we propose a structure/activity relationship based on the free energy of binding or reaction of non-native substrates to evaluate the catalysis relative to that of native substrates. While Brønsted-Evans-Polanyi (BEP) relationships such as that proposed here have found broad application in heterogeneous catalysis, their extension to enzymatic catalysis is limited. We report here on density functional theory (DFT) studies for C–C bond formation and C–C bond cleavage associated with the decarboxylation of six 2-keto acids by a thiamine-containing enzyme (EC and demonstrate a linear relationship between the free energy of reaction and the activation barrier. We then applied this relationship to predict the activation barriers of 17 chemically similar novel reactions. These calculations reveal that there is a clear correlation between the free energy of formation of the transition state and the free energy of the reaction, suggesting that this method can be further extended to predict the kinetics of novel reactions through our computational framework for discovery of novel biochemical transformations.

Calculated vs predicted activation free energy barriers [B3LYP/6-31 G(d)] for both C–C bond-formation and C–C bond breaking between 2-keto acids and ThDP co-factor in dichloroethane dielectric at 298 K


Enzyme catalysisBEP relationshipDensity functional theory

Supplementary material

894_2011_1062_MOESM1_ESM.doc (36 kb)
Table S1Calculated free energy of the reaction (ΔGreaction) and activation free energy barrier (ΔGTS ) for the C–C bond formation and cleavage with ThDP co-factor and various 2-keto acids at 298 K in gas phase using B3LYP/6-31 + G(d) level of theory. Values are reported in kcal/mol. (DOC 35 kb)
894_2011_1062_MOESM2_ESM.doc (42 kb)
Table S2Computed free energy of the reaction, calculated transition state barriers and predicted transition state barriers at the B3LYP/6-31 G(d) level of theory for the C–C bond formation and C–C bond breaking reactions in the gas phase (298 K). Chloro, amino, methoxy and hydroxy substituted pyruvic acid (pyr), 2-keto butanoic acid (but), 2-keto-isovaleric acid (iso), and 2-keto-valeric acid (val) were used for this study. All values are reported in kcal/mol. (DOC 42 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Rajeev Surendran Assary
    • 1
    • 2
  • Linda J. Broadbelt
    • 1
  • Larry A. Curtiss
    • 2
  1. 1.Department of Chemical and Biological EngineeringNorthwestern UniversityEvanstonUSA
  2. 2.Materials Science Division and Center for Nanoscale MaterialsArgonne National LaboratoryArgonneUSA