Protein surface roughness accounts for binding free energy of Plasmepsin II‐ligand complexes

The calculation of absolute binding affinities for protein‐inhibitor complexes remains as one of the main challenges in computational structure‐based ligand design. The present work explored the calculations of surface fractal dimension (as a measure of surface roughness) and the relationship with experimental binding free energies of Plasmepsin II complexes. Plasmepsin II is an attractive target for novel therapeutic compounds to treat malaria. However, the structural flexibility of this enzyme is a drawback when searching for specific inhibitors. Concerning that, we performed separate explicitly solvated molecular dynamics simulations using the available high‐resolution crystal structures of different Plasmepsin II complexes. Molecular dynamics simulations allowed a better approximation to systems dynamics and, therefore, a more reliable estimation of surface roughness. This constitutes a novel approximation in order to obtain more realistic values of fractal dimension, because previous works considered only x‐ray structures. Binding site fractal dimension was calculated considering the ensemble of structures generated at different simulation times. A linear relationship between binding site fractal dimension and experimental binding free energies of the complexes was observed within 20 ns. Previous studies of the subject did not uncover this relationship. Regression model, coined FD model, was built to estimate binding free energies from binding site fractal dimension values. Leave‐one‐out cross‐validation showed that our model reproduced accurately the absolute binding free energies for our training set (R2 = 0.76; =0.55 kcal/mol; SDerror = 0.19 kcal/mol). The fact that such a simple model may be applied raises some questions that are addressed in the article. Linear relationship (r = −0.88) between binding site FD (as measured of active site surface roughness) and binding free energies was observed. Previous studies of the subject did not uncover this relationship. Regression model was built to estimate binding free energies from binding site FD values. Leave‐one‐out cross‐validation showed that our model reproduced accurately the absolute binding free energies for our training set (R2 = 0.76; =0.55 kcal/mol; SDerror = 0.19 kcal/mol).