I think that it would be a shorter jump to try to figure out what a 4.5 D&D would look like... or, even if they avoid calling it "4.5", what 4e looks like after a few Player's Handbooks are under its belt. We can also extrapolate some things from the questions and issues people are having now.
There's a strong possibility that one of the most house ruled and demanded systems will be a crafting system and a professional system. And if I'm not mistaken, they've already acknowledged that mechanics for these might be added down the road. Once 4e has been around for a while, I can see the 4e = MMO criticism gradually going away, clearing the way for them to borrow a valid approach from online games, and have a 'professional class' system. Not as detailed and robust as the core class system, but still essentially giving people the option to be a "Warlock / Blacksmith." Crafting could easily adopt the Skill Challenge system, with charts for making items (a spoon is complexity 1, a longsword is complexity 3, an advanced metal lock is complexity 5, etc.) and the mishaps or progress made in Skill Challenges for each trade skill. You don't have to write individual encounters for the spoon and the longsword, just a general "blacksmith" or "metalworking" one that details what might happen on a failed check. Other than that, you just need a table with a sampling of items and the difficulty thresholds for them. There will probably be house rules circulating along these lines in very short order, and they'll eventually have to come up with their own version of them.
So in a 4.5 or a 5e, that might become a part of the core rules, depending on how well it's received. Offering a few trade skills and Skill Challenge encounters for them in each PHB might take up 10-20 pages at most, easily added.
I think that in terms of core game mechanics, after everyone has time to look at the game for a while, time itself may be looked at - in terms of when and how powers are used out of combat and how time is measured. We might see separate recharge categories for out-of-combat power use, or a more detailed ritual system, or other similar things.
They might even try to have more integration between monsters and PCs. DMs might decide that they are getting sick of their players asking "is it five minutes yet? Can I use it again?" and then adopt something like the die roll for recharge out of combat. Something like that might eventually work it's way into the core mechanics. It's not a huge stretch because we're already seeing things like rolling to determine durations (the new saving throw.) So instead of tracking or guesstimating out-of-combat time in five minute intervals, perhaps your encounter powers recharge on a five or a six on a six-sided die outside of combat.
I think we'll see small changes like that, and they will come mostly from things people start house ruling for themselves.
In terms of how the game is played, I think that it's going to be the opposite of what people think: most people are expecting tabletop games to go extinct and for everything to go the way of MMOs and computer-based gaming. But people have been able to move games to the online environment on their computers for years now, and the tabletop experience isn't going away. We're getting to the point where, rather than moving our activities into the computer room, computers and tech are getting smaller, more convenient to use, and being moved to the places where we do various activities. I think technologies that make high tech table top gaming at home, perhaps with a mix of people sitting at the table and some people virtually present, is more likely than tabletop RPGs going completely to MMO.
When people look to the future, they tend to look at the most advanced item that currently dominates their lives and imagine that as the center of their future lives. It seems to loom larger and larger and dominate. But then things get more portable, and adaptable, and it turns out the future isn't the nuclear family dressed in polyester unitards sitting around a large console TV featuring Smell-O-Vision or interactive shows, it's having a flexible paper-thin display that you snap out and mount wherever it's convenient.
So rather than seeing RPGs move entirely to the computer, I think we're going to see technology move out to wherever we play RPGs.
I know that the guy that mentioned replacing dice with carbon nanotubes was joking, but a lot of materials scientists believe we're only a couple of years away from being able to bring things like flexible, paper-thin LCDs to market and they could be used for digital newspapers you can fold up and so forth. A few recent discoveries I read about over on PhysOrg.com indicated that the technology wasn't very far away from becoming cheap enough mass production and distribution. So imagine a Digital Battlemat: You roll it out, plug it into a portable device like a handheld or laptop, and you display images on it. You can move tokens around on it digitally, or place real miniatures right on top of it. The friend in Guam can connect to you over the Internet, and join the other 3 players who are sitting around the table. You hear his voice, he can move things onto the digital battlemat to display them, and he can move his character's token around on the mat. But everyone else is physically there.