Methods for Theoretical Treatment of Local Fields in Proteins and Enzymes

Abstract

Electric fields generated by protein scaffolds are crucial in enzymatic catalysis. This review surveys theoretical approaches for detecting, analyzing, and comparing electric fields, electrostatic potentials, and their effects on the charge density within enzyme active sites. Pioneering methods like the empirical valence bond approach rely on evaluating ionic and covalent resonance forms influenced by the field. Strategies employing polarizable force fields also facilitate field detection. The vibrational Stark effect connects computational simulations to experimental Stark spectroscopy, enabling direct comparisons. We highlight how protein dynamics induce fluctuations in local fields, influencing enzyme activity. Recent techniques assess electric fields throughout the active site volume rather than only at specific bonds, and machine learning helps relate these global fields to reactivity. Quantum theory of atoms in molecules captures the entire electron density landscape, providing a chemically intuitive perspective on field-driven catalysis. Overall, these methodologies show protein-generated fields are highly dynamic and heterogeneous, and understanding both aspects is critical for elucidating enzyme mechanisms. This holistic view empowers rational enzyme engineering by tuning electric fields, promising new avenues in drug design, biocatalysis, and industrial applications. Future directions include incorporating electric fields as explicit design targets to enhance catalytic performance and biochemical functionalities.