In Magnetic Resonance Imaging (MRI), the Nuclear Magnetic Resonance (NMR) relaxation of water protons is used to examine bodily tissues. To enhance image contrast, Gadolinium-based contrast agents (GBCAs) are employed to reduce water proton relaxation time. However, despite the long history of NMR and MRI, the molecular-scale processes remain poorly understood, and the modeling and interpretation of NMR relaxation physics still rely on severe assumptions. Further complicating the matter, concerns have arisen over the release of Gadolinium(III) ions in the body from GBCAs, which have been linked to renal impairments and bioaccumulation in bones, the brain, and kidneys. Thus, evaluating and improving the relaxivity and chemical stability of MRI chelates is crucial for ensuring both contrast efficacy and safety. In this context, this work employs quantum and classical molecular simulations to provide key molecular insights into NMR relaxivity and the chemical stability of MRI contrast agents. Following the principles of statistical mechanics of stochastic processes, we demonstrate how the NMR relaxation signal from simulations can be decomposed into contributions from dynamical “molecular eigenmodes,” which can be obtained by solving the corresponding Fokker-Planck equation for the system. This technique has the potential to build a library of signals for interpreting NMR and MRI data in otherwise difficult-to-analyze environments. The simulation results are corroborated and validated by NMR relaxation dispersion measurements, showing great agreement with experiments without the necessity of any adjustable parameters. Furthermore, an approach based on the molecular Quasi-Chemical Theory (m-QCT) is presented to assess the solvation free energies of Gadolinium(III) ions and their chelated complexes, addressing the chemical stability of contrast agents. This approach integrates high-level quantum chemistry for short-range interactions with coarse-grained models for long-range effects, enabling a rigorous assessment of chelation thermodynamics, equilibrium constants, and the influence of chelate chemistry and solution conditions on the release of toxic ions.
