To answer my own question, I popped these new 4GB modules in last night. I originally had two 2GB modules in each set of DIMM slots (in positions 1/2 and 5/6). I added the two 4GB modules to each set (in positions 3/4 and 7/8).
Sure enough, the memory slot configuration tool popped up, telling me I had a non-optimal configuration. OSX wanted the 4GB modules in the first slots in each set and the 2GB modules in the second pair of slots. So, I ended up swapping everything with two 4GB modules in the first slots (1/2 and 5/6) and the two 2GB modules in the second slots (3/4 and 7/8) for each set. Boot it up and the memory slot configuration tool informed me that I was now optimal.