Experimental Atom-by-Atom Dissection of Amide-Amide and Amide-Hydrocarbon Interactions in H₂O

Quantitative information about amide interactions in water is needed to understand their contributions to protein folding and amide effects on aqueous processes and to compare with computer simulations. Here we quantify interactions of urea, alkylated ureas, and other amides by osmometry and amide-aromatic hydrocarbon interactions by solubility. Analysis of these data yields strengths of interaction of ureas and naphthalene with amide sp²O, amide sp²N, aliphatic sp³C, and amide and aromatic sp²C unified atoms in water. Interactions of amide sp²O with urea and naphthalene are favorable, while amide sp²O-alkylurea interactions are unfavorable, becoming more unfavorable with increasing alkylation. Hence, amide sp²O-amide sp²N interactions (proposed n-σ* hydrogen bond) and amide sp²O-aromatic sp²C (proposed n-π*) interactions are favorable in water, while amide sp²O-sp³C interactions are unfavorable. Interactions of all ureas with sp³C and amide sp²N are favorable and increase in strength with increasing alkylation, indicating favorable sp³C-amide sp²N and sp³C-sp³C interactions. Naphthalene results show that aromatic sp²C-amide sp²N interactions in water are unfavorable while sp²C-sp³C interactions are favorable. These results allow interactions of amide and hydrocarbon moieties and effects of urea and alkylureas on aqueous processes to be predicted or interpreted in terms of structural information. We predict strengths of favorable urea-benzene and N-methylacetamide interactions from experimental information to compare with simulations and indicate how amounts of hydrocarbon and amide surfaces buried in protein folding and other biopolymer processes and transition states can be determined from analysis of urea and diethylurea effects on equilibrium and rate constants.