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. 2009 Aug;30(11):1701-11.
doi: 10.1002/jcc.21268.

Trypsin-ligand binding free energies from explicit and implicit solvent simulations with polarizable potential

Dian Jiao  1 , Jiajing Zhang, Robert E Duke, Guohui Li, Michael J Schnieders, Pengyu Ren
Affiliations

Trypsin-ligand binding free energies from explicit and implicit solvent simulations with polarizable potential

Dian Jiao et al. J Comput Chem. 2009 Aug.

Abstract

We have calculated the binding free energies of a series of benzamidine-like inhibitors to trypsin with a polarizable force field using both explicit and implicit solvent approaches. Free energy perturbation has been performed for the ligands in bulk water and in protein complex with molecular dynamics simulations. The binding free energies calculated from explicit solvent simulations are well within the accuracy of experimental measurement and the direction of change is predicted correctly in all cases. We analyzed the molecular dipole moments of the ligands in gas, water and protein environments. Neither binding affinity nor ligand solvation free energy in bulk water shows much dependence on the molecular dipole moments of the ligands. Substitution of the aromatic or the charged group in the ligand results in considerable change in the solvation energy in bulk water and protein whereas the binding affinity varies insignificantly due to cancellation. The effect of chemical modification on ligand charge distribution is mostly local. Replacing benzene with diazine has minimal impact on the atomic multipoles at the amidinium group. We have also utilized an implicit solvent based end-state approach to evaluate the binding free energies of these inhibitors. In this approach, the polarizable multipole model combined with Poisson-Boltzmann/surface area (PMPB/SA) provides the electrostatic interaction energy and the polar solvation free energy. Overall the relative binding free energies obtained from the MM-PMPB/SA model are in good agreement with the experimental data.

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Figures

Figure 1
Figure 1
Chemical structures of trypsin ligands studied: A. benzamidine; B. 1,3-diazamidine; C. 1,4-diazamidine; D. 4-amino-benzamidine; E. Benzylamine.
Figure 2
Figure 2
Thermodynamic cycle of relative binding free energy calculation in explicit water MD simulations.
Figure 3
Figure 3
Comparison between experimental and the calculated binding free energies from explicit and implicit solvent calculations (kcal/mol).
Figure 4
Figure 4
Intermolecular hydrogen bonding structure between ligand and trypsin at the binding site, (a) Crystal structure of trypsin in complex with ligand A (PDBID 1BTY). (b) to (e) are representative snapshots from explicit-water molecular dynamics simulations of trypsin with ligand B to E, respectively.
Figure 5
Figure 5
Evolution of the hydrogen bond distances between the ligand and the surroundings: (a) water hydrogen bonding to amidinium N2 from simulations of ligand C and D. A similar water molecule is present in the crystal structure of trypsin-benzamidine; (b) ligand B hydrogen bonding to the Asp 189 residue in the binding pocket.
Figure 5
Figure 5
Evolution of the hydrogen bond distances between the ligand and the surroundings: (a) water hydrogen bonding to amidinium N2 from simulations of ligand C and D. A similar water molecule is present in the crystal structure of trypsin-benzamidine; (b) ligand B hydrogen bonding to the Asp 189 residue in the binding pocket.
Figure 6
Figure 6
The running average of relative free energy changes in trypsin-ligand complex from explicit water MD simulations of ligand B and E. In both cases, the ligand is being perturbed into benzamidine.
Figure 7
Figure 7
The running average of absolute binding free energies of ligand B and E from MM-PMPB/SA. A total of 80 snapshots were extracted at a 2.5 ps interval from the last 200 ps of the explicit water simulation trajectory.
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