Density functional theory and natural bond orbital analysis are used to explore the impact of solvent on hyperconjugation in methyl triphosphate, a model for "energy rich" phosphoanhydride bonds, such as found in ATP. As expected, dihedral rotation of a hydroxyl group vicinal to the phosphoanhydride bond reveals that the conformational dependence of the anomeric effect involves modulation of the orbital overlap between the donor and acceptor orbitals. However, a conformational independence was observed in the rotation of a solvent hydrogen bond. As one lone pair orbital rotates away from an optimal antiperiplanar orientation, the overall magnitude of the anomeric effect is compensated approximately by the other lone pair as it becomes more antiperiplanar. Furthermore, solvent modulation of the anomeric effect is not restricted to the antiperiplanar lone pair; hydrogen bonds involving gauche lone pairs also affect the anomeric interaction and the strength of the phosphoanhydride bond. Both gauche and anti solvent hydrogen bonds lengthen nonbridging O-P bonds, increasing the distance between donor and acceptor orbitals and decreasing orbital overlap, which leads to a reduction of the anomeric effect. Solvent effects are additive with greater reduction in the anomeric effect upon increasing water coordination. By controlling the coordination environment of substrates in an active site, kinases, phosphatases, and other enzymes important in metabolism and signaling may have the potential to modulate the stability of individual phosphoanhydride bonds through stereoelectronic effects.