Solvent PRE and effective near surface electrostatics: theory, methods, and biological insights

Electrostatic interactions are central to biomolecular structure, dynamics, and function, yet experimentally probing local electrostatic potentials with residue-level resolution remains challenging. Solvent paramagnetic relaxation enhancement (sPRE) offers a powerful nuclear magnetic resonance (NMR) approach to directly quantify near-surface electrostatic environments without requiring structural information. In this review, we outline the theoretical framework underlying sPRE, emphasizing recent advances in spectral density analysis, spatial decomposition, and the influence of intermolecular potentials. We discuss the effective near-surface electrostatic potential (ENS), a derived quantity that captures local electrostatic fields by comparing transverse relaxation rates induced by paramagnetic cosolutes of differing charge. Applications to proteins, nucleic acids, and intrinsically disordered systems highlight the ability of sPRE and ENS to reveal electrostatic modulation in complex biological contexts, including phase separation, ion atmosphere structure, and protein-nucleic acid interactions. We also examine current limitations and provide a theoretical basis for interpreting ENS, offering perspectives for future methodological developments in electrostatics mapping by NMR.