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Ivan P. Oliveira, Gabriel E. Jara, Leandro Martínez

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Lipases are enzymes that function at the interface of water and lipids. Here we show that the enzyme displays a mechanism of rapid orientation at the interface, which exposes the catalytic site to the substrates and is followed by the stabilization of the active form of the protein. The structural basis of these mechanisms can be used to guide protein design.
Molecular mechanism of activation of Burkholderia cepacia Lipase at aqueous-organic interfaces

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Lipases are water-soluble enzymes which catalyze the hydrolysis of lipids. Since lipids are mostly hydrophobic, lipase activity occur preferentially at interfaces of aqueous and organic phases. In this work, we study the molecular mechanisms by which the Burkholderia cepacia lipase (BCL) is activated at interfaces of water with octane and with methyl caprylate (CAME). We show that BCL assumes very rapidly a preferential orientation at the interfaces, in which the active site is exposed to the organic phase. With BCL oriented to the interface, we compute the free energy of the aperture of the catalytic pocket using Adaptive Biasing Force MD simulations. The exposure to the organic phase promotes a clear stabilization of the open form of the catalytic pocket relative to the enzyme in water. This stabilization stems from the hydrophobicity of domains U1 and U2, which allow the penetration of organic solvents into the catalytic cleft impeding the closure of the pocket. Our results suggest that the structure and hydrophobicity of BCL are optimized for its activation in biphasic systems through the regulation of the accessibility of the catalytic pocket by, and for, hydrophobic substrates. The understanding of this mechanism may be useful for the design of proteins with targeted activation.


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