I think you are the only person that can answer this question. What is the layout of your favorite game (or game you will be playing most often on this cabinet)?
Personally, I choose the ergomomic way of layout out 4 of my buttons: match the thumb, index, middle, and ring fingers in an arc. I rest my palm on the control panel, and fingers extend to each of these buttons comfortably. I also chose this layout because its the same layout as my favorite game Soul Calibur. Virtua Fighter is also in this layout (but with only 3 buttons). Even though these two games are fighters, this layout is generic enough to be comfotable with any other non-fighting game I have ever played on my cabinet.
Of course I have a lot more buttons on my control panel, but the main 4 are layed out in this fashion. The remaining buttons are combined with the middle & ring finger buttons to form 2 rows of 3 buttons for traditional Street Fighter, Tekken, Capcom... fighters.