The invention provides polypeptides comprising a variant
heavy chain variable framework domain (VFR). In some embodiments, the amino acids defining the VFR form a loop of an
antigen binding pocket. In an embodiment, the polypeptide is a
variable domain of a
monobody and has a variant VFR. The polypeptide may optionally comprise one or more complementary determining regions (CDRs) of
antibody variable domains. In an embodiment, the polypeptide is a
variable domain of a
monobody and has a variant VFR and one or more variant CDRs. Libraries of polypeptides that include a plurality of different
antibody variable domains generated by creating diversity in a VFR, and optionally, one or more CDRs are provided and may be used as a source for identifying novel
antigen binding polypeptides that can be used therapeutically or as reagents. The invention also provides fusion polypeptides, compositions, and methods for generating and using the polypeptides and libraries.