The modulation of water structure by solutes has tremendous scientific and technological consequences. Sugars act as protein stabilizers; however, the mechanisms of their protective effects are still not fully understood. Using a conceptual model, we predict that the better a template a sugar isomer is for cooperative hydration, the higher its hydration number and protein-stabilizing effect will be. We developed a qualitative 2D imitation‑simulation which supports this model, and a unique atomistic simulation that quantifies energetic and spatial compatibility of sugars with ideal tetrahedral water structure, as embodied in hexagonal ice. Studying four isomeric sugars, we found the following order of sugar compatibility with the ice: galactose>glucose>mannose>talose. We postulate that the more compatible the sugar isomer is with the ideal water structure, the better a template it would be for cooperative hydration in liquid aqueous solution. We found the same order for sugar hydration numbers in binary liquid aqueous solutions, for the coil-globule transition of a polymer (poly n-isopropyl acrylamide) in a ternary solution, and for the protective effect of aldohexoses against protein thermal denaturation, supporting our proposed templating concept as fundamental in explaining nonionic solute effect on water structure and on protein stability. This study may pave the way for rationally designing more powerful protein stabilizers, by synthesizing molecules whose structure would be optimized for water-structure templating.
