Abstract: This disclosure provides methods of designing and generating polypeptide variants that have altered properties compared to a parent polypeptide. The present disclosure provides methods of generating polypeptide variants, for example, variant isoprenoid synthases and/or variant prenyl transferases that have at least one desired property not present in the parent polypeptide. The present disclosure further provides polypeptides and polynucleotides encoding variant polypeptides, as well as vectors and host cells comprising the polynucleotides that encode the variant polypeptides. In other embodiments, the present disclosure provides methods of using the variant polypeptides to generate useful products, such as isoprenoid compounds and/or isoprenoid products.