An aptamer can hit its target at single-digit nanomolar and still be useless. The site it found gets buried when the protein joins its complex. Or it sits under a glycan. Or it belongs to a domain that never appears in the fragment of the protein actually circulating in your samples. Or the binding is tight and reproducible and it changes nothing about the process you wanted to control.

Choosing the target protein is only the first decision. The next one is where on that protein the aptamer should bind, and what should happen when it does.

The previous article, The proteome doesn't have a coverage gap – it has a coverage bias, described three reasons proteins fall outside large measurement panels: they are hard to present in native form, they resemble their relatives too closely, or they exist as several biologically distinct forms that assays cannot separate. All three come back at the design stage, only now as questions about which patch of surface to aim at.