The way I approach fine-tuning DOT layout is to add subgroups where it seems appropriate, add a 1px border for the subgroup and see where the layout engine is situating it next to other nearby vertices/edges. Sometimes I may have to put a border around a few subgroups, then attempt to adjust size of vertices and entire area to nudge it to a local minima. Note: I don't attempt to adjust the size of the subgroups, I'm not sure that even works anyway, but maybe it depends on the choice of layout algorithm, too. Padding and other style on the vertex-box may help, too. It's been a few years for me, tbh.
Deciding where the appropriate subgroups are is a bit of an art. Sometimes it's obvious, as in bipartite graphs that are intentionally bipartite. Or, if there is a staged layout like for pipeline architectures. Sometimes it's not obvious even when it seems it should be, like when graphviz really wants to make a certain edge really short. Be ready to backtrack sometimes. Then I usually remove the subgroup border after I'm done, but a few times they have been useful to leave there.
One thing I really like about DOT is that adding hyperlinks to the vertices and edges that translate decently into the compiled output is really nice. I had an oncall dashboard that made liberal use of this feature that I still think back on fondly sometimes.