Solvent-induced lid opening in lipases: a molecular dynamics study

Area of Science:

• Biochemistry
• Molecular Biology
• Enzymology

Background:

• Lipases possess a mobile lid covering the substrate binding site, typically in an inactive, closed conformation.
• Interfacial activation, triggered by hydrophobic environments, leads to lid opening and enzyme activity.

Purpose of the Study:

• To elucidate the molecular mechanism of interfacial activation in three distinct lipases.
• To investigate the role of solvent environment in regulating lipase lid conformation and activity.

Main Methods:

• Employed multiple molecular dynamics simulations of 25 ns for lipases from Candida rugosa, Rhizomucor miehei, and Thermomyces lanuginosa.
• Simulations utilized both closed and open lipase structures in aqueous and organic (toluene) solvents without restraints.
• Analyzed conformational transitions and stability of lid structures across different solvent conditions.

Main Results:

• Closed lipases in water showed no conformational changes.
• Simulations in toluene induced gradual lid opening in closed lipase structures, indicating solvent-driven activation.
• Open structures remained stable in toluene but reverted to a closed, partially unfolded state in water.

Conclusions:

• Lipase lid opening and closing are primarily driven by the surrounding solvent environment.
• The conformational changes are independent of substrate binding, highlighting the critical role of solvent polarity.
• Identified potential kinetic bottlenecks in the conformational transition pathways.