An ab initio computational protocol for including polarization effects in molecular mechanics point-charges for a whole protein is introduced. The method involves Quantum Mechanics/Molecular Mechanics calculations on all protein residues followed by parametrization of lectrostatic-potential (ESP) atomic charges to reproduce the electrostatic field of the QM/MM electronic charge density. This process is performed iteratively until convergence. The method is illustrated on several proteins showing a remarkable improvement in the electrostatic potential description when compared with standard fixed-charge force field. The method scales linearly with the size of the system, and provides a protein-specific charge distribution based on rigorous first principle calculations.
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