End-point free energy calculations using MM-GB(PB)SA provide a detailed understanding of molecular recognition in protein-ligand interactions. The binding free energy can be used to rank-order protein-ligand structures in virtual screening for compound or target identification.  Here, we carry out free energy calculations for a diverse set of 11 proteins bound to 14 small molecules using more than a microsecond of explicit-solvent MD simulation. The structure of these complexes was previously solved by crystallography and their binding studied with isothermal titration calorimetry (ITC) data enabling direct comparison to the MM-GB(PB)SA calculations.  Four MM-GBSA and three MM-PBSA calculations reproduced the ITC free energy within 1 kcal�mol-1.  MM-GBSA exhibited better rank-ordering with a Spearman r of 0.68 compared to 0.40 for MM-PBSA. The SVRKB scoring function (derived using Support Vector Regression using binding affinity and structural data) applied to MD snapshots resulted in excellent rank-ordering (r = 0.81). Calculations of the configurational entropy using normal mode analysis resulted in free energies that correlated significantly better to the ITC free energy than the MD-based quasi-harmonic approach, but the computed entropies showed no correlation with the ITC entropy. When the adaptation energy is taken into consideration by running separate simulations for complex, apo and ligand (MM-PBSAADAPT), there is less agreement with the ITC data for the individual free energies, but remarkably good rank-ordering is observed (r = 0.89).  Interestingly, filtering MD snapshots by pre-scoring protein-ligand complexes with a machine learning-based approach (SVMSP) resulted in a significant improvement in the MM-PBSA results from r = 0.40 to r = 0.81. Finally, the non-polar components of MM-GB(PB)SA, but not the electrostatic components, showed strong correlation to the ITC free energy.

Molecular recognition in a diverse set of protein-ligand interactions studied with molecular dynamics simulations and end-point free energy calculations

246th National Meeting (2013)

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