Thursday, March 15, 2012

New paper: A Computational Methodology to Screen Activities of Enzyme Variants

Martin just submitted his paper to PLoS ONE and deposited it at

PM6 is a qualitative step forward for semiempirical methods ability to predict correct reaction mechanisms and hydrogen bonding geometry.  Given the computational speed of PM6 this means that barrier heights now can be estimated very efficiently for large systems such as enzyme-catalyzed reactions. In this paper we present a computation methodology that does just that, and use it to screen for mutants that lower the barrier height.   As far as I can tell this is the first method that can do that.

We present a fast computational method to efficiently screen enzyme activity. In the presented method, the effect of mutations on the barrier height of an enzyme-catalysed reaction can be computed within 24 hours on roughly 10 processors. The methodology is based on the PM6 and MOZYME methods as implemented in MOPAC2009, and is tested on the first step of the amide hydrolysis reaction catalyzed by Candida Antarctica lipase B (CalB) enzyme. The barrier heights are estimated using adiabatic mapping and shown to give barrier heights to within 3kcal/mol of B3LYP/6-31G(d)//RHF/3-21G results for a small model system. Relatively strict convergence criteria (0.5kcal/(mol Å)), long NDDO cutoff distances within the MOZYME method (15 Å) and single point evaluations using conventional PM6 are needed for reliable results. The generation of mutant structure and subsequent setup of the semiempirical calculations are automated so that the effect on barrier heights can be estimated for hundreds of mutants in a matter of weeks using high performance computing.

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