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Computational Modelling of a Lipase at a Hydrophobic Substrate Interface

Principal Investigator: Jürgen Pleiss, Institute of Technical Biochemistry, University of Stuttgart (Germany)
HPC Platform: Hermit of HLRS

Water molecules are directly involved in many enzymatic reactions. Scientists of the Institute of Technical Biochemistry of the University of Stuttgart developed a simulation method to model the influx of water molecules from the outside into a deeply buried active site of a protein. They applied this method to a lipase attached to its substrate interface.

Lipases catalyze the hydrolysis of water-insoluble triglycerides (fats and oils) by attaching to an oil droplet. In order for a chemical reaction to take place, an oil molecule diffuses through a substrate channel to a catalytically active site inside the lipase. To break an oil molecule, a water molecule is needed. Because the substrate is hydrophobic, it is not evident how the water molecules can reach the active site.

By extensive molecular dynamics simulations, the researchers found that water can access the active site by two major pathways: it leaks in via the substrate channel and it is guided by dedicated water channels which lead from the outside to the active site inside the lipase. It has been shown previously that blocking a water channel changes the catalytic activity of the lipase. Using this information, a lipase can be engineered which catalyses preferentially the reverse reaction: synthesis of a structured triglyceride or a fatty acid ester rather than its degradation by hydrolysis.

A realistic model system with a lipase molecule attached to the interface between water and oil was created and extensively simulated to explore the functionally relevant conformations of the lipase at the interface. The GROMACS 4.5.3 software with the OPLS-AA all-atom force field and the Berger lipid model was used. Over 300 simulations, including benchmark and test runs, were performed. In total, more than 1μs of molecular dynamics simulations were conducted on a system consisting of 100,000 atoms using the Hermit cluster of the High Performance Computing Center (HLRS) in Stuttgart, Germany.

Research Team:

Sven Benson, Jürgen Pleiss - Institute of Technical Biochemistry, University of Stuttgart


Benson, S.P., Pleiss, J.: Solvent flux method (SFM): a case study of water access to Candida antarctica lipase B. J. Chem. Theory Comput. 10, 5206–5214 (2014)

Computational Modelling of a Lipase at a Hydrophobic Substrate InterfaceCopyright: ITB, University of Stuttgart (Germany)

Scientific Contact:

Prof. Dr. Juergen Pleiss
Institute of Technical Biochemistry
University of Stuttgart
Allmandring 31, D-70569 Stuttgart (Germany)
e-mail: Juergen.Pleiss [at]

February 2016