A lot of it is due to Aeroscreen but a bit of it is just due to pure nature of the car. If you've ever ridden bikes it's as close to a bike experience as you can get in a car.
You're right though setup does play a factor. There are people on goldwings who can ride across country and there are people on supersports that hurt after 50 miles.
I have Aeroscreen, sequential straight cut transmission, fiberglass seats, no doors or half doors. I'm in the extreme of self abuse.
Otherwise suspension is stock and 13in tires.
Quite a bit of it is mental wearing too. Most of my long hauls are on the highway and it's not relaxing one bit. You need death grip on steering wheel as a bump on the road can steer you off the road (tires tracking, that's my alignment setting) and nobody sees you so you drive like you're invisible and then they see you and they really see you and start taking pictures and now you have to mind that on top.
Mentally it's a lot.
I'm sure I can relax more on a nice back road cruise but I haven't done many of those. City commute and highway otherwise.