This paper discusses the sequence/structure relation. The core question concerns the degree to which similar
sequences produce similar structures and vice versa. A mechanism by which similar sequences may result in
dissimilar structures is proposed, based on the Fuzzy Oil Drop (FOD) model in which structural similarity is estimated
by analyzing the protein’s hydrophobic core. We show that local changes in amino acid sequences, in addition to
producing local structural alterations at the substitution site, may also change the shape of the hydrophobic core,
significantly affecting the overall tertiary conformation of the protein. Our analysis focuses on four sets of proteins:
1) Pair of designer proteins with specially prepared sequences; 2) Pair of natural proteins modified (mutated) to
converge to a point of high-level sequence identity while retaining their respective wild-type tertiary folds; 3) Pair
of natural proteins with common ancestry but with differing structures and biological profiles shaped by divergent
evolution; and 4) Pair of natural proteins of high structural similarity with no sequence similarity and different
biological function.