Abstract: The ?-trefoil protein human fibroblast growth factor-1 (FGF-1) is made up of a six-stranded anti-parallel ?-barrel closed off on one end by three ?-hairpins, thus exhibiting a three-fold axis of structural symmetry. The N- and C-termini ?-strands hydrogen bond to each other and are postulated from both NMR and X-ray structure data to represent a structurally-weakened region of the ?-barrel. Val mutations within the N- and C-termini ?-strands are shown to stabilize the structure and to increase van der Waals contacts by filling local cavities present within this region. Mutations that increase van der Waals contacts between both the N- and C-termini ?-strands are generally associated with significant reductions in the unfolding kinetics, and also increase the cooperativity of unfolding. Surprisingly, several mutant polypeptides herein disclosed greatly exceed the wild-type polypeptide in ability to stimulate human fibroblasts to proliferate.