I imagine there are not many things with unexpected shapes at that level that aren't accounted for somehow. Anything that doesn't slot into it perfectly will get knocked away by collisions. Bad shapes do exist however (prions) and are a cause of diseases.

Generally bulky substrates are inefficient and require additional catalysts for binding. (Typically kinases.)

So something with an unexpected tail won't react. It will not occlude the receptor either because it won't bind with it reliably...

These things are very, very precise.