How many simultaneous inputs do you need? One? Then obviously optimize for one handed. Left or right? ;-) Last time I played a mobile game, the controls could be pulled around on the screen.
If you need two simultaneous, than you obviously can't go for one thumb.
A trivia comes to mind. I somewhere heard that when Word of Warcraft was released it was designed to be playable with one hand, because in Asia there are many people smoking with one hand and playing with the other. So they used that mouse gesture of clicking both buttons for forward movement, that is usually done on keyboard.