Hyperpolarized NMR Combined with Quantum Mechanical Simulations Reveal Atomistic Structures of Calcium Phosphate Prenucleation Clusters.

The discovery of solute precursors of crystalline materials, such as biominerals, recently challenged the classical nucleation theory (CNT). One emerging method for investigating these early-stage intermediates in solution is dissolution dynamic nuclear polarization (dDNP)-enhanced nuclear magnetic resonance (NMR) spectroscopy. Recent applications of dDNP to calcium carbonate (CaC) and calcium phosphate (CaP) mineralization have demonstrated the feasibility of identifying and tracing very early-stage prenucleation clusters (PNCs). However, the structural details remain difficult to resolve as dDNP is mainly limited to simple one-dimensional NMR detection. To overcome this bottleneck, we herein integrate hyperpolarized NMR of PNC with molecular dynamics simulations and quantum mechanical calculations to gain atomistic structural insights into CaP PNCs. By simulating the PNC structures, computing chemical shift parameters, and comparing these to hyperpolarized NMR "fingerprint" spectra, we demonstrate how to derive models of solution-state structural ensembles of PNC, even when very short-lived. With this approach, we find that the Ca/P