I recently ran On The Run for a small group who had never played Shadowrun before, and they got through with minimal prodding from me. They bypassed certain elements-- for instance, they never even spoke to Loomis-- but they managed to get out of the run with the maximum amount of money earned and minimal hassle. They sold the songs to JetBlack's people and then participated in the bloodbath to recover the files, thereby selling the only copy to Darius.
I can see how it would be easy for a group to just complete the quest and miss on the whole second half of the run, but I think most players will tend to lean toward more curious than power gamey.
As far as advice, make sure the team covers a variety of roles, and give every player a spotlight moment. I also ran the game in two four hour sessions so they had plenty of time to poke around if they wanted. Otherwise, just make sure to read the whole thing through and review the sections you're likely to run in the session just before, and maybe make yourself some notes of the big stuff, but those are all suggestions from in the book.