Accurate and Efficient Calculation of Protein-Ligand Interaction Energies Using an Electrostatically Embedded...

Accurately determining protein-ligand binding free energy is critical for drug design but requires computationally expensive quantum-mechanical (QM) calculations. Fragmentation methods can mitigate this cost, yet their accuracy hinges on properly modeling the polarizing chemical environment. Here we present an application and refinement of the Electrostatically Embedded Generalized Molecular Fractionation with Conjugate Caps (EE-GMFCC) approach, termed EE-GMFCC[P-L], for computing protein-ligand interaction energies. Our method efficiently obtains the total QM energy by linearly combining the energies of capped fragments embedded in a protein point-charge field and the pairwise interactions between non-neighboring fragments. After systematically investigating methodological parameters, including ligand charge, capping scheme, and basis set, we employed the approach to calculate interaction energies for a benchmark set of 21 protein-ligand systems. The resulting data set provides a high-accuracy standard for developing and validating more approximate computational methods in structure-based drug design.