Enzyme-Synthetic Inhibitor Specific Interactions Study by a New Non-equilibrium Molecular Dynamics Method

Abstract

Most of the molecular modeling methods are using molecular modeling algorithms that may involve either the exhaustive exploration of all possible ligand conformations and their relative position according to the enzyme. The purpose of this study was to apply the Jarzinsky method, a non-equilibrium molecular dynamics method that supposes the pull by an external force of a specific region in the investigated system and the record of the pulling force for a specific amount of time, conveniently chosen.

In the present situation, the simulations were directed on the analysis of the interaction between the synthetic inhibitor Batimastat (as ligand) and the Zn-dependent enzyme, neutrophil collagenase metalloproteinase-8.

We considered useful to apply a new method, borrowed from computational physics, and poorly used until recently in molecular modeling studies for biological molecules.

The simulation followed the evolution of the coupled system MMP-Batimastat for a specific time of 125 ps, during while we have recorded the pulling force profile.

The first step appears at a force of approximately 400 kJ/mol*nm and its result is represented by a local destructuration of the polypeptidic chain packed as α-helix on which the Zn2+ ion is bound at the Glu-114 residue.

The second step consist in the inhibitor removal from the Zn2+ ion and its migration in the solution, migration that is associated with a rapid decrease of the pulling force magnitude, toward values that correspond with friction forces between the inhibitor and the surrounding solvent layers. This behavior demonstrates the importance of the Zn2+ ion in the binding process between the metalloproteinases catalytic site and the specific synthetic inhibitors. Our results shown the Zn ion roles in the inhibitor binding process and also that the used method has a wide potential in investigating mutual interactions between biological.