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ResearchMolecular Dynamics GroupResearch

Computational enzyme design


Computational enzyme design holds great promise for providing new biocatalysts for synthetic chemistry. Recent successes with de novo computational protein design and redesign of enzyme active sites suggest that computational methods can be used for controlling enzyme functionality.

We collaborate with the Biocatalysis group of Dick Janssen to establish a high-throughput computational framework aimed at rational enzyme design. To engineer enzyme stereoselectivity, we introduced the CASCO strategy (CAtalytic Selectivity by COmputational design), and to improve thermostability, we developed the FRESCO (Framework for Rapid Enzyme Stabilization by COmputational libraries) approach. Both methods require far less screening than conventional directed evolution.

[1] H.J. Wijma, R.J. Floor, S. Bjelic, S.J. Marrink, D. Baker, D.B. Janssen. Enantioselective Enzymes by Computational Design and In Silico Screening Angew. Chem., 127:3797-3801, 2015
[2] M.M. Heberling, M.F. Masman, S. Bartsch, G.G. Wybenga, B.W. Dijkstra, S.J. Marrink, D.B. Janssen. Ironing out Their Differences: Dissecting the Structural Determinants of a Phenylalanine Aminomutase and Ammonia Lyase ACS Chem. Biol., 10:989-997, 2015
[3] H.J. Wijma, S.J. Marrink, D.B. Janssen. Computationally efficient and accurate enantioselectivity modeling by clusters of molecular dynamics simulations J. Chem. Inf. Model.,54:2079–2092, 2014
[4] R.J. Floor, H.J. Wijma, D.I. Colpa, A. Ramos-¬Silva, P.A. Jekel, W. SzymaƄski, B.L. Feringa, S.J. Marrink, D.B. Janssen. Computational library design for increasing haloalkane dehalogenase stability ChemBioChem, 15:1660-1672, 2014
[5] H.J. Wijma, R.J. Floor, P.A. Jekel, D. Baker, S.J. Marrink, D.B. Janssen. Computationally designed libraries for rapid enzyme stabilization PEDS, 27:49-58, 2014

CASCO design of a pair of enantiocomplementary epoxide hydrolases for the enantioselective transformation of cyclopentene oxide (1a) to yield either (R,R)- or (S,S)-cyclopentane-1,2-diol. Predicted structures of the active sites of limonene epoxide hydrolase variants pro-RR-8 (A) and pro-SS-16 (B). The docked substrate 1a is shown in yellow. The water molecule performing the nucleophilic attack is also shown. Residues that were introduced to prevent substrate binding in the undesired pose are labeled in bold.
CASCO design of a pair of enantiocomplementary epoxide hydrolases for the enantioselective transformation of cyclopentene oxide (1a) to yield either (R,R)- or (S,S)-cyclopentane-1,2-diol. Predicted structures of the active sites of limonene epoxide hydrolase variants pro-RR-8 (A) and pro-SS-16 (B). The docked substrate 1a is shown in yellow. The water molecule performing the nucleophilic attack is also shown. Residues that were introduced to prevent substrate binding in the undesired pose are labeled in bold.
Last modified:25 June 2015 12.52 a.m.