AFAIK, there are just two design parameters that need to change to go from gasoline to E100:
  1. the fuel-air ratio;
  2. elimination of any plastic/rubber components from the fuel system that may be attacked by E100.

The second issue is obviously the more difficult design change. A modern engine can probably change its fuel/air ratio with a simple parametric tweak to its software.

Also have to deal with vaporization or atomization issues of ethanol at cold temps, the fuel must be preheated a bit, just like in an alcohol stove. Im sure fuel injection helps a great deal with this, but for small motors injection isnt always practical. IIRC the change in fuel-air ratio is big enough that your average run of the mill production car fuel system might not quite be able to have enough volume to be ok with just a software change, depends on how much "headroom" the engineers left in the system.
AFAIK, there are just two design parameters that need to change to go from gasoline to E100:

I think the most important is the compression ratio. Increasing the compression ratio has been shown to improve gas mileage of E85 vehicles. Instead of a 25% drop in fuel efficiency, they only have a 15% or so drop.

25% and 15% per gallon though.  What should we look at it we want to judge ethanol vs gasoline as a automotive fuel ... miles per Calorie or BTU?

I'd think we'd want to know the conversion efficiency from chemcial potential energy to practical kinetic energy.