I am left-handed. When I first put a video game controller in my hand, I began to play games and it never felt weird. When I went to the arcades, I played with the controller in my left hand with the buttons on the right, and it never felt any different. I never had to adapt to anything because that is how I had always learned to play games. The only difference is that my dominant hand(left) allows me better control over the joystick. In the arcades, there is no need for very much dexterity with the right hand in most situations although I'm sure you could find a few games in which being right-handed would be better than being left-handed. Having said that, it makes me wonder if the creator of the current conrol panel layout (joystick on the left, buttons on the right) was left-handed so lefties would have an advantage when controlling games because the dominant hand would be used for all movement in most games.
The crazy thing is that I've had to learn to use a right-handed yoke when I play flight simulator games in the arcade so accuracy in my right hand is probably equal or better than my left hand. I can play a game with a joystick in my left or right hand and it doesn't feel weird at all. That's the benefit of being left handed and having to learn in a right-handed world; I can do most things with both hands. In fact, most ambidextrous individuals were left-handed at some point, and they slowly converted to using both hands. I'm left-hand dominant, but I could do everything with my right hand with no problems at all if something were to happen to my left arm. (chopped off for stealing in Osama's homeland, caught in an elevator door, etc)....but that's another topic for another day in another forum. To answer your question, I prefer the joystick on the left and the buttons on the right because I play a lot of fighting games. Trying to perform a long combo in Killer Instinct with the layout switched would be most difficult.