AbstractThe thermodynamic properties derived earlier for the formation of side‐chain hydrogen bonds were re‐evaluated, taking into account medium effects and interactions of the side chains with nearby nonpolar groups. In determining the enthalpy of formation of the hydrogen bond, competitive hydrogen bonding with water has to be considered, except for “buried” groups, i.e., groups surrounded entirely by nonpolar groups. For such buried groups, the earlier estimate of ΔH H°= −6 kcal./mole is still valid, but for groups exposed to water, a lower value has to be used, estimated to be −1.5 kcal./mole. The internal bond rotations of side chains involved in hydrogen bonding are not restricted completely; therefore, ΔS H°is only −2 to −5 e.u. per side chain, instead of the much higher values estimated earlier. As a result, the new estimated value of ΔF H°is 0 to −0.5 kcal./mole, not much different from the earlier estimate. The ease of hydrogen bond formation may be changed by cooperative or competitive hydrophobic bonding of the nonpolar portions of the polar side chains with the backbone or nearby nonpolar side chains. Various cases of such interactions are discussed, including the burying of polar groups and the formation of hydrogen bonds between buried groups. It is shown that, in aqueous environment, the polar groups form more than one hydrogen bond with water, an effect to be taken into account when considering buried groups. Medium effects due to the presence of nonpolar groups and the effects of changes in the water structure on the ease of formation of the α‐helix are mentioned. Estimates for the thermodynamic parameters of the various hydrogen‐bonding and hydrophobic interactions are given. It is shown that hydrophobic interactions will, in general, enhance the strength of hydrogen bonds. The net free energy of formation of a simple structure involving both interactions may range from about −0.5 to −2.4 kcal./mole. It may reach much more highly negative values for large structures. The corresponding ranges of the net enthalpy and entropy of formation are −1.5 to −0.5