I took a look at UAE and at first glance, it reminds me very much of VirtualBox and similar virtual machine setups. Very heavyweight, fine grained configuration, lots of bells and whistles.
I'm struggling to figure out how to create a user experience that combines that approach with the MAMEUI "machine picker" approach without compromising the advantages of both sides. You wouldn't want someone browsing dozens of random arcade games to have to set up a profile for some random Pac Man clone.
Perhaps there should be a tabbed view, one tab being "Machines" and the other being "Profiles"? Right clicking on a machine could have a menu item for "Create Profile From Machine", with richer configuration? BletchMAME could even ensure that images and perhaps even saved state persist across sessions?