Development of AMOEBA Polarizable Force Field for Rare-Earth La3+ Interaction with Bioinspired Ligands

Rare-earth metals (REMs) are crucial for many important industries, such as power generation and storage, in addition to cancer treatment and medical imaging. One promising new REM refinement approach involves mimicking the highly selective and efficient binding of REMs observed in relatively recently discovered proteins. However, realizing any such bioinspired approach requires an understanding of the biological recognition mechanisms. Here, we developed a new classical polarizable force field based on the AMOEBA framework for modeling a lanthanum ion (La3+) interacting with water, acetate, and acetamide, which have been found to coordinate the ion in proteins. The parameters were derived by comparing to high-level ab initio quantum mechanical (QM) calculations that include relativistic effects. The AMOEBA model, with advanced atomic multipoles and electronic polarization, is successful in capturing both the QM distance-dependent La3+-ligand interaction energies and experimental hydration free energy. A new scheme for pairwise polarization damping (POLPAIR) was developed to describe the polarization energy in La3+ interactions with both charged and neutral ligands. Simulations of La3+ in water showed water coordination numbers and ion-water distances consistent with previous experimental and theoretical findings. Water residence time analysis revealed both fast and slow kinetics in water exchange around the ion. This new model will allow investigation of fully solvated lanthanum ion-protein systems using GPU-accelerated dynamics simulations to gain insights on binding selectivity, which may be applied to the design of synthetic analogues.