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Google details its protein-folding software,

academics offer an alternative
Once computationally impossible, AIs now translate protein sequence to
structure.
JOHN TIMMER - 7/18/2021, 9:45 PM
University of Washington

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Thanks to the development of DNA-sequencing technology, it has become trivial to obtain the
sequence of bases that encode a protein and translate that to the sequence of amino acids that make
up the protein. But from there, we often end up stuck. The actual function of the protein is only
indirectly specified by its sequence. Instead, the sequence dictates how the amino acid chain folds
and flexes in three-dimensional space, forming a specific structure. That structure is typically what
dictates the function of the protein, but obtaining it can require years of lab work.

For decades, researchers have tried to develop software that can take a sequence of amino acids and
accurately predict the structure it will form. Despite this being a matter of chemistry and
thermodynamics, we've only had limited success—until last year. That's when Google's DeepMind AI
group announced the existence of AlphaFold, which can typically predict structures with a high degree
of accuracy.

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At the time, DeepMind said it would give everyone the details on its breakthrough in a future peer-
reviewed paper, which it finally released yesterday. In the meantime, some academic researchers got
tired of waiting, took some of DeepMind's insights, and made their own. The paper describing that
effort also was released yesterday.

The dirt on AlphaFold

DeepMind already described the basic structure of AlphaFold, but the new paper provides much more
detail. AlphaFold's structure involves two different algorithms that communicate back and forth
regarding their analyses, allowing each to refine their output.

One of these algorithms looks for protein sequences that are evolutionary relatives of the one at
issue, and it figures out how their sequences align, adjusting for small changes or even insertions and
deletions. Even if we don't know the structure of any of these relatives, they can still provide
important constraints, telling us things like whether certain parts of the protein are always charged.

The AlphaFold team says that this portion of things needs about 30 related proteins to function
effectively. It typically comes up with a basic alignment quickly, then refines it. These sorts of
refinements can involve shifting gaps around in order to place key amino acids in the right place.

The second algorithm, which runs in parallel, splits the sequence into smaller chunks and attempts to
solve the sequence of each of these while ensuring the structure of each chunk is compatible with the
larger structure. This is why aligning the protein and its relatives is essential; if key amino acids end up
in the wrong chunk, then getting the structure right is going to be a real challenge. So, the two
algorithms communicate, allowing proposed structures to feed back to the alignment.

The structural prediction is a more difficult process, and the algorithm's original ideas often undergo
more significant changes before the algorithm settles into refining the final structure.

Perhaps the most interesting new detail in the paper is where DeepMind goes through and disables
different portions of the analysis algorithms. These show that, of the nine different functions they
define, all seem to contribute at least a little bit to the final accuracy, and only one has a dramatic
effect on it. That one involves identifying the points in a proposed structure that are likely to need
changes and flagging them for further attention.

The competition
In an announcement timed for the paper's release, DeepMind CEO Demis Hassabis said, "We pledged
to share our methods and provide broad, free access to the scientific community. Today, we take the
first step towards delivering on that commitment by sharing AlphaFold’s open-source code and
publishing the system’s full methodology."

But Google had already described the system's basic structure, which caused some researchers in the
academic world to ponder whether they could adapt their existing tools to a system structured more
like DeepMind's. And, with a seven-month lag, the researchers had plenty of time to act on that idea.

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The researchers used DeepMind's initial description to identify five features of AlphaFold that they felt
differed from most existing methods. So, they attempted to implement different combinations of
these features and figure out which ones resulted in improvements over current methods.

The simplest thing to get to work was having two parallel algorithms: one dedicated to aligning
sequences, the other performing structural predictions. But the team ended up splitting the structural
portion of things into two distinct functions. One of those functions simply estimates the two-
dimensional distance between individual parts of the protein, and the other handles the actual
location in three-dimensional space. All three of them exchange information, with each providing the
others hints on what aspects of its task might need further refinement.

The problem with adding a third pipeline is that it significantly boosts the hardware requirements, and
academics in general don't have access to the same sorts of computing assets that DeepMind does.
So, while the system, called RoseTTAFold, didn't perform as well as AlphaFold in terms of the accuracy
of its predictions, it was better than any previous systems that the team could test. But, given the
hardware it was run on, it was also relatively fast, taking about 10 minutes when run on a protein
that's 400 amino acids long.

Like AlphaFold, RoseTTAFold splits up the protein into smaller chunks and solves those individually
before trying to put them together into a complete structure. In this case, the research team realized
that this might have an additional application. A lot of proteins form extensive interactions with other
proteins in order to function—hemoglobin, for example, exists as a complex of four proteins. If the
system works as it should, feeding it two different proteins should allow it to both figure out both of
their structures and where they interact with each other. Tests of this showed that it actually works.

Healthy competition
Both of these papers seem to describe positive developments. To start with, the DeepMind team
deserves full credit for the insights it had into structuring its system in the first place. Clearly, setting
things up as parallel processes that communicate with each other has produced a major leap in our
ability to estimate protein structures. The academic team, rather than simply trying to reproduce what
DeepMind did, just adopted some of the major insights and took them in new directions.

Right now, the two systems clearly have performance differences, both in terms of the accuracy of
their final output and in terms of the time and compute resources that need to be dedicated to it. But
with both teams seemingly committed to openness, there's a good chance that the best features of
each can be adopted by the other.

Whatever the outcome, we're clearly in a new place compared to where we were just a couple of years
ago. People have been trying to solve protein-structure predictions for decades, and our inability to
do so has become more problematic at a time when genomes are providing us with vast quantities of
protein sequences that we have little idea how to interpret. The demand for time on these systems is
likely to be intense, because a very large portion of the biomedical research community stands to
benefit from the software.

Science, 2021. DOI: 10.1126/science.abj8754

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Google details its protein-folding software, academics offer an alternative... https://arstechnica.com/science/2021/07/google-details-its-protein-foldin...

Nature, 2021. DOI: 10.1038/s41586-021-03819-2  (About DOIs).

READER COMMENTS 44 SHARE THIS STORY

JOHN TIMMER
John became Ars Technica's science editor in 2007 after spending 15 years doing biology research at
places like Berkeley and Cornell.

EMAIL jtimmer@arstechnica.com // TWITTER @j_timmer

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