Ab initio structure prediction for long amino acid sequence

Yes, you’re exactly correct. It’s likely that the 500 aa protein is not a single cooperatively folding domain. Instead, it’s possible that those 500 amino acids are divided up into several independently folding domains. (Or there’s one independently folded domain in the midst of intrinsically disordered sections.) You can then predict the domains independently, and then attempt to combine the domain models later.

How best to divide up the sections is a bit of a black art. There are a number of different prediction methods up there. If I recall correctly, the approach used by the Robetta server is called “ginzu”. I’m not sure exactly how to run it, though. As this is a strictly sequence-based approach, Rosetta proper isn’t really involved. I’d do some literature searches to see what the state of the art is in domain parsing. (Really any approach can be used as a pre-processing step before feeding the split sequences into Rosetta.)

By the way, I’d highly recommend doing something like a BLAST search of your protein against the PDB databases. You might not have the entire protein with homology to an existing structure, but if you find a particular domain or subsection of the seqeunce with a decent homology to an already solved structure, you can use the more efficient homology modeling protocols in Rosetta to model those domains, leaving you a much smaller segment to have to model with ab initio methods.

If this is a eukaryotic protein, I’d also recommend running something like DISOPRED or another intrinsically-disordered structure prediction program. This will give you a better sense of where the secondary structure elements are and where potentially unstructured regions are. If there’s significant segments of disorder, you can trim those out prior to predicting the structure, as the disordered regions probably will deliniate the independently folding domains. (Assuming something like a “beads on a string” model. If there’s a disordered insertion into the middle of a domain it could be hard to tell.)