UK Catalysis Hub


Multiscale modelling for biocatalysis

Prof Adrian Mulholland

Biomolecular simulations have advanced to the stage where they can provide reliable predictions of enzyme mechanisms, selectivity, thermoadaptation and inhibition. Simulation can identify mechanisms of catalysis in biosynthesis [1] and antibiotic resistance [2], and analyse problems relevant to biocatalysis such as the chemoselectivity of alkene oxidation by bacterial cytochrome P450 enzymes. Simulations can identify and characterise catalytic interactions [3] and determinants of chemo-, regio- and stereospecificity [4]. Increasingly, simulations are contributing to the design and engineering both of natural enzymes and of de novo biocatalysts [5,6]. Classical molecular dynamics (MD) simulations can allow predictions of substrate binding, and reveal and predict dynamical changes associated with thermoadaptation and temperature optima of enzyme catalytic activity [7]. For modelling reactions within large systems such as proteins, combined quantum mechanics/molecular mechanics (QM/MM) methods are a good, practical approach, e.g. for modelling transition states and reaction intermediates, and to analyse structural and electronic determinants of reactivity. QM/MM methods treat the active site with a QM electronic structure method, while the effect of the enzyme environment is included by a simpler (MM) approach. Projector-based embedding techniques allow highly accurate correlated ab initio QM methods to be applied in QM/MM calculations [8].

  1. The Catalytic Mechanism of a Natural Diels-Alderase Revealed in Molecular Detail M.J. Byrne et al. JACS 138, 6095-8 (2016)
  2. Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1 P. Hinchliffe et al. Scientific Reports 7, 39392 (2017)
  3. A catalytic role for methionine revealed by a combination of computation and experiments on phosphite dehydrogenase K.E. Ranaghan et al. Chemical Science 5 2191-2199 (2014)
  4. Reaction mechanism of N-acetylneuraminic acid lyase revealed by a combination of crystallography, QM/MM simulation, and mutagenesis. A.D. Daniels et al. ACS Chem Biol. 9 1025-32 (2014)
  5. Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme J.R. Anderson et al., Nature Communications 8 Article number: 358 (2017)
  6. Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase Vijaykumar Karuppiah et al. ACS Catalysis 7 6268–6282 (2017)
  7. Dynamical origins of heat capacity changes in enzyme catalysed reactions, M. van der Kamp et al., Nature Communications, in press (2018)
  8. A Projector-Embedding Approach for Multiscale Coupled-Cluster Calculations Applied to Citrate Synthase S.J. Bennie et al. J. Chem. Theory Comput. 12 2689–2697 (2016)