Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

The binding of a series of hydroxamate inhibitors with gelatinase-A is examined to evaluate the viability of
calculating free energies of binding, ΔGb, utilizing molecular dynamics (MD) simulations with a linear
interaction energy approach. In our simulations, a bonded model was used to represent the potentials of the
catalytic zinc center. The electrostatic distribution of this model was derived using a two-stage electrostatic
potential fitting calculations. The resulting bonded model was then used to generate the MD trajectories.
Coulombic, van der Waals, and coordinate bond energy components determined from MD simulations of the
bound and unbound inhibitors solvated in water were correlated with the free energies of binding for the 15
hydroxamate inhibitors. In the correlation process, several linear models consisted of different energy
components were tested. We found that besides the usually used Coulombic and van der Waals energy terms,
the introduction of a constant term could significantly improve the correlation. The best model yields an
average error of 0.6 kcal/mol for the 15 binding affinities, which cover an observed range of 7.2 kcal/mol.
The predictive ability of the best model was revealed by the high value of q2 (0.854) from the leave-one-out
cross-validation. To this series of inhibitors, the constant term can be treated as effective adjustment to the
entropy contribution in the binding free energies. The MD simulations predicted the binding mode of the
gelatinase-A with the studied inhibitors, and also provided insights into the interactions occurring in the
active site and the origins of variations in ΔGb. The P1‘ groups of inhibitors make extensive van der Waals
and hydrophobic contacts with the nonpolar side chains of four residues in the S1‘ subsite, including Leu
197, Val 198, Leu 218, and Tyr 223, which directly influence the ligand binding. Hydrogen bonds between
hydroxamates and gelatinase-A are very important to stabilize the inhibitors in the active site. The hydrogen
bonds between the P3‘ group and gelatinase-A can produce more favorable electrostatic interactions.