To date there hasn’t been a lot of effort put into separating design from function, in the Mastodon code. The new 2.0 release seems to have some theming options, which may make it a lot easier to ‘skin’ a Mastodon instance.
I’ve dabbled a bit with Halcyon, which is a Twitter-clone UI for Mastodon, but it isn’t made to be a drop-in replacement for Mastodon, and requires users to re-authenticate with Mastodon to use Halcyon as an app with an auth token.
There’s also the Mastodon API which allows the (very) technically minded to craft their own UI from scratch, but that’s a huge job with a moving target as Mastodon is still piling on the new features.
I’m hoping 2.0 gives me the tools to make my instance more MINE. I agree about the 3-column layout, but I’ve a hundred other things I also want to tweak.