2001: A Space Odyssey is both a Big Ideas SF story and a look at the practicalities of space travel, with astronauts’ routines examined in detail on the way to confront an alien artefact. It’s quite a balancing act, which arguably ends once we get to that “ultimate trip” sequence. How do you top discovering the meaning of life? How do you depict it at all? The trip is one answer...
And how do you follow it?
Arthur C. Clarke returned to the setting in later novels (and one film) and provided an origin for the monolith, focusing on the practicalities of humanity moving out into space. Before that, another sequel had been created by Jack Kirby, adapting the film for comics and then carrying on with further stories of monoliths influencing primitive people and super-evolving their descendants in space. They run off in wildly different directions, neither of which feel all that much like the film as a whole. Neither does the film of 2010. Star Trek: The Motion Picture feels closer, with the chilly tone and the huge effects sequences authored by Douglas Trumbull helping it almost like an impression of 2001 with the characters from Star Trek intruding and asking the questions Kubrick never has voiced - what does God need with a monolith? Ahem.
Were I to try following 2001, I would try to mix the two facets in a story of humanity stepping out into space. I’d avoid including a killer A.I. as that seems too close.
And I would definitely, definitely keep the indications of contact with another intelligence mysterious. Glimpses, strange non-communications. Give them a coherent agenda but make sure they never spell it out.
And to bring this back to gaming...
Unbelievably, both 2001 and 2010 had official Star Frontiers adventure books. Apparently 2001 was a replay of the film where the players were expected to play the main characters and stick pretty close to the plot, while 2010 was less reverent. TSR were doing something similar with Indiana Jones around the same time, with players expected to play the stars, but at least there they adapted the comics for adventures as well as just the films.