Evolution discovered a bunch of structural patterns at different layers (fragments, folds..) that are energetically favorable, versatile, easily foldable, robust to mutations and then kept reusing them. As a result it sampled more and more in these parts of the space. That's why the fold space is uneven.
Are there any folds and patterns that evolution evolution has not discovered that are also useful? I think Baker Group created a bunch of new folds. I'm not sure if they are as useful as the one discovered by Evolution. After all, Evolution had more compute power than us.
And it seems very few proteins appear to be significant problems.
The most famous is the prion protein which can misfold in ways to cause a variety of contagious diseases. Like mad cow disease, chronic wasting disease, scrapie and in humans CJD and vCJD, fatal familial insomnia, Kuru, GSS.
Perhaps because misfoldings of the prion protein can convert others but why is it all affecting that same protein? Always baffled me why aren't other/many proteins suspitible to becoming a prion?
There are others we call "prionoid" because they can have shades of the catetrosphic misfolding prion can.
Evolution takes surprisingly little time to home in on solutions which are durable enough to handle local conditions. It's not demonstrably good at preparing its offspring for anything that would be useful outside the local environment. It also has a way of forgetting anything before the most recent data set (or global reset).
Our compute capacity isn't deployed to brute force Monte Carlo sims (mostly). So it's apples and oranges.
This reminds of the fact that certain fundamental proteins get created even if the DNA for them has errors.
The thinking is that evolution created error correction for the critical proteins to account for mutations.
Fascinating stuff.