The assembly of the type I procollagen heterotrimer is initiated by an interaction between the carboxyl propeptides, with triple helix folding proceeding in the C→N direction. The pro-α1-(I)-C-propeptides can interact with self to form the homotrimer or with pro-α2(I)-C-propeptide to establish the heterotrimer. The two propeptides are similar in length and have about 65% identity in sequence. Nevertheless, we proposed that differences in interaction between propeptides might account for thein vivo selection of heterotrimer formation rather than homotrimer formation. To test this hypothesis we have determined the probable structures of the human C-propeptides by molecular modeling and energy minimization using Molecular Simulations Insight, Discover 95.0/3.0, and Biopolymer programs. The propeptide structures were constrained with the two known intrachain disulfide bonds in each case. The two structures were globally similar, with three distinct structural domains (G-I, L, G-II) in each case. A few crucial Pro residues and other sequence differences, however, produced different structures in each domain. The different interaction profiles of the three domains may be of crucial importance for heterotrimer selection.