Performing Effective Calculations of Protein-Ligand Binding Free Energy with the Help of Molecular Dynamics Methods

Aims: In our study, we aimed to calculate the binding free energies using molecular dynamics methods with the help of biased sampling approach using the binding site residues in protein - ligand complexes.

Methodology: Molecular modeling and dynamics methods such as Steered Molecular Dynamics (SMD) and Umbrella Sampling (US) were used in our studies. Systems to be simulated were prepared using the binding site residues and ligands. In order to perform SMD simulations, the systems were reoriented to allow the ligands to be pulled in the z-axis direction. The poses of the system were recorded while the ligands were drawn in the z-axis direction (reaction coordinate). Using the poses selected from the reaction coordinates, 1 ns molecular dynamics simulations were performed for each selected pose using the umbrella sampling method. The results obtained from US simulations were evaluated through the Gromacs Wham module and the binding free energies of the ligands were calculated.

Results: The binding free energies of the complexes we investigate were calculated as -7.23±1.75 for the 1NFU, -9.73±1.83 for the 2JS4, -9.16±2.53 for the 1FJS, -8.63±0.17 for the 1F0R and -13.76±2.47 kcal/mol for the 1KSN complexes. Experimental values binding free energies of the complexes mentioned were reported as -10.63, -10.47, -10.14, -10.51 and +12.90 kcal/mol, respectively. The bias between the binding free energy values we obtained and the experimental data vary between 0.8 kcal/mol (1FJS) and 3.4 kcal/mol (1NFU). In addition, there is a regression coefficient of 0.80 between our calculated binding free energies and the experimental results.

Conclusion: The high regression coefficient between the binding free energies we determined in our study and the experimental results and the low bias of numerical differences of the binding free energies show that our approach gives positive results.