This is why I absolutely despise any vehicle that makes you go through several touch screen menus to adjust HVAC controls.Others have touched on this factor; and that is if anything about the vehicle is mentally fatiguing it adds up to overall fatigue from driving.
For example, my Mazda CX 5 is normally a very comfortable car to drive. But the other day I had to make a 75 mile drive in the rain with the last 35 miles being on a 2 lane mountain road. The rain conditions were constantly changing and none of the intermittentent windshield wiper settings seemed to match the rain conditions. So that required almost constant adjustments to the wiper controls. I was also going through some thick patches of fog which required intense concentration to see the road and also watch out for oncoming drivers. The windows would fog up inside and I needed to use the defogger function and then shut it off again.
So in other words besides having to make almost constant adjustments to the various vehicle settings, there was also a lot of concentration and stress involved in keeping safe and a lot of steering wheel movement on the winding roads. I was really exhausted by the time I got home.
If your car needs constant adjustments while driving, that will add up in a negative way. On the other hand you don't want the car to lull you into inattentiveness. I like to be engaged with my vehicle while driving but road, weather and traffic conditions can make a short drive seem like a marathon too.