Well, real operations are just more careful.
When you do one simulation run in Orbiter you do nothing else than NASA. But NASA does many simulation runs on their computers until they have values which are so good, that they can launch the real thing.
The Computer inside the Shuttle is a great tool, but it is not smart at all: It needs the simulation results and ground computations for calculating it's maneuvers.
The Relative Navigation mode (rendezvous with a space station by using star trackers and radar) of the Shuttle is the most autonomous operation, which can run completely without ground data, but generally, the data calculated that way, is compared and improved by ground data.
Still, the shuttle moves much more careful as you would do in Orbiter - they could reach the ISS in a single direct burn theoretically, but this consumes more fuel when something is wrong, than a slow careful approach, which respects possible errors.
During launch, as this was specially asked, there are many different automatic systems active, as well as a large crew on the ground.
You have the launch processing system, which gets used by the ground crew to automatically open valves, activate systems etc. You have the GLS, which does a similar job as the LPS, but runs almost completely without human interaction. You have the onboard computers running as redundant set, for the last 10 seconds of the countdown, starting engines and after lift-off, calculating already closed-loop solutions, even though the guidance is still open-loop during SRB burn time. As soon as the SRBs separate, the control loop get's closed, the solution for main engine cut-off calculated, and when found, the Shuttle follows it's solution. The target for the main engine cut-off is calculated on the ground before the launch, the same applies to all following OMS maneuvers: The nominal targeting data for these burns is calculated before the countdown even started, written on the data tapes which are used inside the Shuttle for loading the computer programs (Called "I-Load").
basically, when you want to fly a perfect mission like the real world shuttle, you have 10 test and simulation flights, and then fly the real mission, with the maneuver data you gained during the earlier simulations.