Not my area of expertise particularly but;
1. I don’t think you can use a structure prediction tool to really ‘validate’ HMMER predictions. I’m pretty sure most structure predictors are relying on HMMER or similar HMM based approaches (Martin told me AlphaFold leans on HHBlits API calls for example). I would argue that the HMM’s are probably ‘closer to the raw data’ and really you’re validating a prediction with HMMs rather than the other way around – though this is a fairly nitpicky point (and all data in concert together is never a bad thing).
2. Generally the whole sequence, but there’s no one size fits all answer. If its a very large protein, or has domains that are not well characterised, then you may get better results feeding in separate domains. The predictor ITASSER, for instance, actually has a hardcoded limit of 1500 AAs, so if your protein is too large, you’d have no choice but to break it up. The larger the sequence you submit, the more likely the simulation will be of lower accuracy generally.
3. Not really sure on this, so others may weigh in. I believe the github page offers a Docker image with alphafold ready to run. I have a vague recollection of there being a webserver available but don’t know for certain offhand.
4. I’m not aware of ‘short-cuts’ per se (but again, not my area of expertise). As mentioned, I know part of the alphafold API calls out to the HHSuite set of tools. I don’t know that this would be any less accurate though, as HHSuite is a very …