Choosing the single fatal flaw of the prequels is tricky, because there so many large problems that overlap, but if I had to think of one, its ultimately that we never really got to know ore care about these characters.
Anakin's basically split into kid and teenager versions, the first being a bland youngster with no depth and the second being an adolescent asshole who seems irritated and frustrated by everyone but Padme. With Luke we got a feel what he wanted, and how he felt about the world around him; we got a look into his dreams. Anakin is defined entirely by his affection for his wife/mother and his lust for power. Other than some little comments about democracy, there's not much else to him.
And Obi-Wan doesn't fare much better. He's likable by virtue of not being a violent murderer or complete idiot who doesn't see the obvious, but there's no arc or really deep insight into him either. There's more depth via the writing and Alec Guiness' acting in the first two acts of A New Hope then there are in three prequel films. Him going from slightly cocky and rash mentor to a calm and collected knight would have made us care about him, and would have helped to understand the person he is the original films.
Finally the writing does no favors for Padme, who's given some goals in her want of peaceful democracy in the Republic, but so many of her scenes involve her coming across as just flat and stilted. She says a lot of things, but her tone and overall demeanor lacks both the warmth and fiery edge of Leia. Even when talking about her planet suffering and dying she comes across like she's a bored office worker doing a presentation about saving money on paperclips.
The elements of her being a supposed determined, intelligent, and caring public servant feel so cosmetic that it ceases being real to an audience. That she becomes less and less of an actual character and more of a plot device to bring Anakin to the dark side as the films go on only makes things worse. It seems like that from the very start her basic template was bringing about Anakin's fall and being anti-dictatorship because her daughter was (will be?) in the original films. Its ironic that a character who Lucas had free range to write about (because she wasn't constrained by the same plot points of Anakin/Obi-Wan) has so little done with her.