I know there are variables for a weapon's handedness (ie, whether it requires one or two hands), but is it possible to change the value using a simple script, or are they read-only values?

I believe it is read-only, though I also believe that a one-handed weapon will be grasped by both hands if it is the only thing in the actor's hands.

I could very well be wrong on both accounts.

I'm pretty sure you're right on the latter - set a weapon to have a very high NoSupportFactor or whatever, then use it with a shield, and your accuracy should drop immensely compared to wielding it without the shield.

As for the former, I'm not sure - can't really test it myself since I don't know enough Lua to try. Ideally, I'd want to be able to toggle a weapon between single/both hand wielding using a pie menu option.

According to the wiki, it's only accessible with a getter function HeldDevice:IsOneHanded()

Your only option is hacky replacing of the weapon with a different one.