The physical basis for how macromolecules regulate the onset of mineral formation in calcifying tissues is not well established. A popular conceptual model assumes the organic matrix provides a stereochemical match during cooperative organization of solute ions. In contrast, another uses simple binding assays to identify good promoters of nucleation. Here, we reconcile these two views and provide a mechanistic explanation for template-directed nucleation by correlating heterogeneous nucleation barriers with crystal-substrate-binding free energies. We first measure the kinetics of calcite nucleation onto model substrates that present different functional group chemistries (carboxyl, thiol, phosphate, and hydroxyl) and conformations (C11 and C16 chain lengths). We find rates are substrate-specific and obey predictions of classical nucleation theory at supersaturations that extend above the solubility of amorphous calcium carbonate. Analysis of the kinetic data shows the thermodynamic barrier to nucleation is reduced by minimizing the interfacial free energy of the system, γ. We then use dynamic force spectroscopy to independently measure calcitesubstrate-binding free energies, ΔG b . Moreover, we show that within the classical theory of nucleation, γ and ΔG b should be linearly related. The results bear out this prediction and demonstrate that low-energy barriers to nucleation correlate with strong crystal-substrate binding. This relationship is general to all functional group chemistries and conformations. These findings provide a physical model that reconciles the long-standing concept of templated nucleation through stereochemical matching with the conventional wisdom that good binders are good nucleators. The alternative perspectives become internally consistent when viewed through the lens of crystal-substrate binding.B iological systems are unique in their ability to organize minerals into functional materials with complex patterns and architectures. A substantial body of evidence suggests specialized macromolecules, particularly proteins (1, 2) and carbohydrates (3, 4), provide preferential sites for nucleation to direct the placement, timing, and orientation of crystals (5), both intra-and extracellular. Within the biomineralization community, the conventional view of biologically directed nucleation is that macromolecular matrices present an interfacial match to the crystal lattice that assists in forming the crystal nucleus. This cooperative view of directed nucleation is rooted in the collective action of multiple residues that guide the organization of ions into a configuration defining the energetic minimum for the system. A series of in vitro observations have reinforced this picture by showing that highly ordered organic monolayers can control the location and orientation of calcite crystals precipitated from solution (6). In this approach, good templates are revealed through a direct functional assay, i.e., nucleation. Over the years, this view of mineralization, both in the context of natural stru...

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Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the precise mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring, and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8 (9)-EpETrE in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.