A method of forming a library of fibronectin Type 3 domain polypeptides, the method comprising (i) aligning BC, DE, and FG amino acid loop sequences in a collection of native fibronectin Type 3 domain polypeptides, (ii) segregating the aligned loop sequences according to loop length, (iii) for a selected loop and loop length from step (ii), performing positional amino acid frequency analysis to determine the frequencies of amino acids at each loop position, (iv) for each loop and loop length analyzed in step (iii), identifying at each position a conserved or selected semi-conserved consensus amino acid and other natural-variant amino acids, (v) for at least one selected loop and loop length, forming: a library of coding sequences that encode, at each loop position, the consensus amino acid, and if the consensus amino acid has an occurrence frequency equal to or less than at least 50%, a single common target amino acid and any coproduced amino acids, to produce a library of walk-through mutagenesis sequences, or a library of coding sequences that encode at each loop position, a consensus amino acid and, if the consensus amino acid has a frequency of occurrence equal to or less than at least 50%, other natural variant amino acids, including semi-conserved amino acids and variable amino acids whose occurrence rate is above a selected minimum threshold occurrence at that position, or their chemical equivalents to produce a library of natural-varient combinatorial sequences, (vi) incorporating the library of coding sequences into framework FN3 coding sequences to form an FN3 expression library, and (vii) expressing the FN3 polypeptides of the expression library to form, as relevant a library of walk-through mutagenesis sequences, or a library of natural-variant combinatorial sequences. (i) aligning BC, DE, and FG amino acid loop sequences in a collection of native fibronectin Type 3 domain polypeptides, (ii) segregating the aligned loop sequences according to loop length, (iii) for a selected loop and loop length from step (ii), performing positional amino acid frequency analysis to determine the frequencies of amino acids at each loop position, (iv) for each loop and loop length analyzed in step (iii), identifying at each position a conserved or selected semi-conserved consensus amino acid and other natural-variant amino acids, (v) for at least one selected loop and loop length, forming: a library of coding sequences that encode, at each loop position, the consensus amino acid, and if the consensus amino acid has an occurrence frequency equal to or less than at least 50%, a single common target amino acid and any coproduced amino acids, to produce a library of walk-through mutagenesis sequences, or a library of coding sequences that encode at each loop position, a consensus amino acid and, if the consensus amino acid has a frequency of occurrence equal to or less than at least 50%, other natural variant amino acids, including semi-conserved amino acids and variable amino acids whose occurrence rate is above a selected minimum threshold occurrence at that position, or their chemical equivalents to produce a library of natural-varient combinatorial sequences, a library of coding sequences that encode, at each loop position, the consensus amino acid, and if the consensus amino acid has an occurrence frequency equal to or less than at least 50%, a single common target amino acid and any coproduced amino acids, to produce a library of walk-through mutagenesis sequences, or a library of coding sequences that encode at each loop position, a consensus amino acid and, if the consensus amino acid has a frequency of occurrence equal to or less than at least 50%, other natural variant amino acids, including semi-conserved amino acids and variable amino acids whose occurrence rate is above a selected minimum threshold occurrence at that position, or their chemical equivalents to produce a library of natural-varient combinatorial sequences, (vi) incorporating the library of coding sequences into framework FN3 coding sequences to form an FN3 expression library, and (vii) expressing the FN3 polypeptides of the expression library to form, as relevant a library of walk-through mutagenesis sequences, or a library of natural-variant combinatorial sequences.