Photoshop, Promotion, and it's ilk have a thin bar on the left of the canvas for selecting tools. All the other controls get docked to the right of the canvas. I consider that a right handed interface.
My gripes with 4 pen colors boils down to 2 issues:
1. It's foreign – If I pick up any other graphics app I can reasonably expect it to have two colors. When I saw the screenshot of the UI, I was confused. I had to read your posts for an explanation of their use, and I had to reason out how and why I would need them. All in all I found it non-obvious and non-intuitive. Not offensively so, mind you. But it still felt foreign.
2. It's a solution to a non-problem – I have never once say down in front of a pixel editor and felt the need for more pen colors. I think this mirrors the issues the Office developers faced when they sat down and made guesses about what the average user wants and doesn't want, without any actual feedback from the users. It seems like a feature that in theory sounds like it would be useful, but in practice is not useful, or is even detrimental.
My ideal workflow is one which has a quickly accessible color picker and key bindings to increment and decrement the current palette index. This makes it easy to both grab an existing color from the canvas and to move through my organized color ramps without having to mouse over to the palette. The only time I need to defer to the actual palette is when I am modifying colors or reorganizing my palette. It is of utmost importance that I can navigate about my palette while keeping my cursor, and my concentration within the canvas, not in the ancillary panels.
Have said that, if you really think 4 pen colors will be a genuine boon to pixel artists, implement it. I'll be the first to happily admit that I was wrong if it improves my art.