Accelerating RESP Charge Calculation With Density Fitting

Despite the widespread success of the restrained electrostatic potential (RESP) method in molecular simulations, its high computational cost due to dense molecular electrostatic potential (MEP) sampling limits its application in large‐scale systems. Here we present DF‐RESP, which combines the density fitting MEP (DF‐MEP) method with RESP charge derivation to dramatically accelerate calculations while maintaining accuracy. Compared to conventional RESP calculations, DF‐RESP achieves excellent accuracy with a mean absolute error (MAE) in charges below 0.003 e for the S22 benchmark and electrostatic interaction energy deviations under 0.1 kcal/mol. For androgen receptor–ligand complexes, DF‐RESP achieves an MAE of less than 0.06 kcal/mol. Notably, DF‐RESP precisely captures conformational energy variations in Ser‐Ala‐Gly tripeptide dynamics through charge analysis and achieves a 14‐fold speedup for the 1493‐atom protein 1h59 while maintaining comparable accuracy. These results demonstrate that DF‐RESP is a computationally efficient and reliable approach for RESP charge calculations in large‐scale biomolecular simulations.