My professor posed this question to the class today - "How do DNA binding proteins specifically bind to base pairs?"

He alluded to the different arrangements of hydrogen-bond donor and acceptors in A-T, T-A, C-G, and G-C base pairs. However, they are not always significantly different in some pairs (i.e. the minor groove of the C-G and G-C base pairs have the same acceptor - donor - acceptor pattern).

So how would a binding protein know the difference between C-G and G-C on the minor groove of a DNA base pair? How does a DNA binding protein know it's reached the right base pair, more generally?

Thank you!