Active site design coupled with binary patterning is a simple, robust method for creating self-assembling functional proteins. Cofactor binding can be guided computationally, biomimetically, or using simple metal-ligand interactions. A new bioinformatic analysis of natural heme cofactor binding sites is introduced, and its application in the creation of high affinity heme, porphyrin and porphyrin-like macrocycles is presented. Application of this analysis toward the creation of artificial hemoglobins, oxygen-activating enzymes and solar energy conversion will be discussed.