4 ms·

> it was not doing homology modelling as it is generally understood, but ab initio protein structure prediction. Maybe according to the current definition of t

by timr 5y ago

> it was not doing homology modelling as it is generally understood, but ab initio protein structure prediction. Maybe according to the current definition of the term, which has drifted over the years. Homology modeling and "ab initio" structure prediction have been drifting toward each other for a long time. These days, the categories are separated by (an essentially arbitrary) sequence identity threshold. If you have a protein sequence with high homology to some other protein with a structure, then you're homology modeling. If you have no matches at all, you're doing "ab initio". In the middle, you have a gray area where you can mix the approaches and call it whatever you like. This is not a pedantic point. If your method requires homology -- however distant and fragmented -- in order to work, then you're always limited to the knowledge in the database. Maybe we've sampled enough of protein space to get the major folds, but certainly, the databases don't have enough information to get the small details right. I have never been a huge believer in the idea that we can go directly from protein sequence to protein structure simply using a mathematical model of physics, but that is the original meaning of "ab initio structure prediction", and if you could do it, it would be far more valuable than alphafold. At risk of making a trivially nerd-snipable metaphor, it's kind of like the difference between google translate and a theoretical model of human intelligence that understands concepts and can generate language. The latter is obviously immensely more capable than the former.

dekhn 5y ago
If CASP is calling methods that use any sequence similarity (the grey area) 'ab initio', that's disingenuous and intellectually dishonest. ab initio means from nothing, and at most, you're allowed to have physically inspired force fields, not sequence similarity to known structures. I put a lot of effort into improving the state of the art in that area, but ultimately concluded it made more sense to concentrate experimental structural determination in the area that was most useful- in proteins that had unknown folds or no known homology (see https://scholar.google.com/citations?view_op=view_citation&hl=en&user=TFgipkIAAAAJ&citation_for_view=TFgipkIAAAAJ:Y0pCki6q_DkC https://scholar.google.com/citations?view_op=view_citation&h... for some previous work I did in this area).
- timr 5y ago
  > If CASP is calling methods that use any sequence similarity (the grey area) 'ab initio', that's disingenuous and intellectually dishonest. The category is given the name, not the methods. People can use any method they like to solve the structures. The organizers are not zealots. The ab initio portion of CASP consists of proteins that the organizers know have low sequence identity to anything in the existing databases. They represent proteins that are "difficult" to solve using what any practitioner might call homology modeling. That doesn't mean that you can't use a method that takes into account the biological databases -- and essentially all of the good methods do! For example, the Rosetta method has competed in both the homology modeling and the ab initio categories for many years. They mix a bit of both -- using homology models to get the fold, and fragment insertion to model the floppy bits. I haven't paid close attention to CASP in a long time, but I assume the competitor list still has tons of entries from people who cling tightly to the purist vision of ab initio modeling. They don't tend to do very well.
  - dekhn 5y ago
    OK, be aware the person you're correcting has: competed in CASP (on a competitor team with Sali), and published papers with Baker on Rosetta methods (my paper is cited in the most RoseTTA paper). "They mix a bit of both -- using homology models to get the fold, and fragment insertion to model the floppy bits." that's the best description of what I believe AF2 is doing, but that AF2 is being marketed as not depending on any sequence similarity. If the CASP folks really are saying "if you have 20% sequence identity and use the structure from that alignment it's ab initio"... that's really just totally misleading. Of course, even ab initio methods are parameterized on biological information; for example, I used AMBER to do MD simulations and many of the force field terms were determined using spectroscopic data from fragments of biological models. That, however is ab initio, because nothing even as large as a single amino acid is parameterized. I'm not saying there's anything wrong with homology modelling, or that the purist vision of ab initio is right. For practical purposes, exploiting subtle structural information through sequence alignment is a very nice way to save enormous amounts of computer time.
    - 5y ago

by timr 5y ago

dekhn 5y ago

If CASP is calling methods that use any sequence similarity (the grey area) 'ab initio', that's disingenuous and intellectually dishonest. ab initio means from nothing, and at most, you're allowed to have physically inspired force fields, not sequence similarity to known structures. I put a lot of effort into improving the state of the art in that area, but ultimately concluded it made more sense to concentrate experimental structural determination in the area that was most useful- in proteins that had unknown folds or no known homology (see https://scholar.google.com/citations?view_op=view_citation&hl=en&user=TFgipkIAAAAJ&citation_for_view=TFgipkIAAAAJ:Y0pCki6q_DkC https://scholar.google.com/citations?view_op=view_citation&h... for some previous work I did in this area).

timr 5y ago
> If CASP is calling methods that use any sequence similarity (the grey area) 'ab initio', that's disingenuous and intellectually dishonest. The category is given the name, not the methods. People can use any method they like to solve the structures. The organizers are not zealots. The ab initio portion of CASP consists of proteins that the organizers know have low sequence identity to anything in the existing databases. They represent proteins that are "difficult" to solve using what any practitioner might call homology modeling. That doesn't mean that you can't use a method that takes into account the biological databases -- and essentially all of the good methods do! For example, the Rosetta method has competed in both the homology modeling and the ab initio categories for many years. They mix a bit of both -- using homology models to get the fold, and fragment insertion to model the floppy bits. I haven't paid close attention to CASP in a long time, but I assume the competitor list still has tons of entries from people who cling tightly to the purist vision of ab initio modeling. They don't tend to do very well.
- dekhn 5y ago
  OK, be aware the person you're correcting has: competed in CASP (on a competitor team with Sali), and published papers with Baker on Rosetta methods (my paper is cited in the most RoseTTA paper). "They mix a bit of both -- using homology models to get the fold, and fragment insertion to model the floppy bits." that's the best description of what I believe AF2 is doing, but that AF2 is being marketed as not depending on any sequence similarity. If the CASP folks really are saying "if you have 20% sequence identity and use the structure from that alignment it's ab initio"... that's really just totally misleading. Of course, even ab initio methods are parameterized on biological information; for example, I used AMBER to do MD simulations and many of the force field terms were determined using spectroscopic data from fragments of biological models. That, however is ab initio, because nothing even as large as a single amino acid is parameterized. I'm not saying there's anything wrong with homology modelling, or that the purist vision of ab initio is right. For practical purposes, exploiting subtle structural information through sequence alignment is a very nice way to save enormous amounts of computer time.
  - 5y ago