[HN Gopher] SimpleFold: Folding proteins is simpler than you think
       ___________________________________________________________________
        
       SimpleFold: Folding proteins is simpler than you think
        
       https://arxiv.org/abs/2509.18480
        
       Author : kevlened
       Score  : 216 points
       Date   : 2025-09-26 18:01 UTC (4 hours ago)
        
 (HTM) web link (github.com)
 (TXT) w3m dump (github.com)
        
       | kylehotchkiss wrote:
       | > Folding Proteins Is Simpler Than You Think
       | 
       | Then why do we need customized LLM models, two of which seemed to
       | require the resources of 2 of the wealthiest companies on earth
       | (this and google's alphafold) to do it?
        
         | wrs wrote:
         | How simple did you think it was before?
        
           | kylehotchkiss wrote:
           | Not simple! Wasn't/Isn't X-ray crystallography what it
           | usually takes to determine the structure?
        
         | wrsh07 wrote:
         | Folding proteins is pretty valuable and this model is
         | comparably small
         | 
         | This doesn't seem like particularly wasteful overinvestment.
         | 
         | Granted, I'm more excited about the research coming out of arc
        
           | jjtheblunt wrote:
           | what are you referring to by arc?
        
             | ben_w wrote:
             | Not op, but I presume the ARC prize/ARC-AGI series of
             | tests: https://arcprize.org/
        
             | hirenj wrote:
             | Arc institute probably.
        
         | aDyslecticCrow wrote:
         | Its not an LLM, It's a transformer. I know the terms are really
         | being butchered in media, but if we're gonna use the term LLM
         | instead of AI, we better make sure it's actually a "large
         | language model" that is being refereed to. If you're unsure,
         | call it a neural net, or machine learning algorithm, or AI.
         | 
         | It's indeed a large model. But if you knew the history of the
         | field, it's a massive improvement. It has progressed from a
         | almost "NP" problem only barely approachable with distributed
         | cluster compute, to something that can run on a single server
         | with some pricey hardware. The smallest model is only here is
         | only 100M parameters and the largest is 3B parameters, that's
         | very approachable to run locally with the right hardware, and
         | easily within the range for a small biotech lab (compared to
         | the cost of other biotech equipment)
         | 
         | It's also (i'd argue) one of the only truly economically and
         | sociably valuable AI technologies we've found over the past few
         | years. Every simulated protein fold is saving a biotech company
         | weeks of work for highly skilled biotech engineers and very
         | expensive chemicals (In a way that that truly only supplement
         | rather than replace the work). Any progress in the field is a
         | huge win for society.
        
           | kylehotchkiss wrote:
           | I'm more teasing the title than the tech :) I'm all for
           | innovation in the field especially with so much bio funding
           | cut!
        
       | barbarr wrote:
       | Why is apple doing protein folding?
        
         | mabedan wrote:
         | Prowlly cuz Siri didn't work out
        
         | Forbo wrote:
         | Reputation laundering?
        
           | jama211 wrote:
           | What's there to launder? Perhaps they shouldn't have as good
           | a reputation as they do, but you can't deny they do have a
           | good reputation.
        
             | amelius wrote:
             | Reputation of what? They are just an office appliance
             | company.
        
               | axoltl wrote:
               | You're confusing your opinion of the company with the
               | perception by the general public. Apple's definitely not
               | perceived as 'an office appliance company' by your
               | average person. It's considered a high-end luxury brand
               | by many[1].
               | 
               | 1: https://www.researchgate.net/publication/361238549_Con
               | sumer_...
        
               | robotresearcher wrote:
               | I think their public sales data shows Apple sells mainly
               | to consumers, and mainly iPhones at that.
               | 
               | Like 1980s SONY, they are the top of the line consumer
               | electronics giant of the time. The iPhone is even more
               | successful than the Walkman or Trinitron TVs.
               | 
               | They also sell the most popular laptops,to consumers as
               | well as corporate. Like SONY's VAIO but more popular
               | again.
        
               | robotresearcher wrote:
               | The move in consumer electronics leadership from Japan to
               | the US, Korea, and now China is probably pretty
               | interesting to understand.
               | 
               | Can anyone recommend a good book or article about this?
        
           | EasyMark wrote:
           | They have a much better reputation that most companies. I
           | think they're doing okay compared to google, facebook,
           | oracle, etc. Few people are going to think a corp is "doing
           | good" but reputation does still matter somewhat.
        
         | IncreasePosts wrote:
         | They're jealous they haven't won a Nobel prize
        
         | nextos wrote:
         | Local inference. I imagine they have an interest in making this
         | and other cutting edge models small enough to be possible to do
         | quick inference on their desktop machines. The article shows
         | that, with Figure 1E demonstrating inference on an M2 Max 64
         | GB.
         | 
         | Frankly, it's a great idea. If you are a small pharma company,
         | being able to do quick local inference removes lots of barriers
         | and gatekeeping. You can even afford to do some Bayesian
         | optimization or RL with lab feedback on some generated
         | sequences.
         | 
         | In comparison, running AlphaFold requires significant
         | resources. And IMHO, their usage of multiple alignments is a
         | bit hacky, makes performance worse on proteins without close
         | homologs, and requires tons of preprocessing.
         | 
         | A few years back, ESM from Meta already demonstrated that
         | alignment-free approaches are possible and perform well.
         | AlphaFold has no secret sauce, it's just a seq2seq problem, and
         | many different approaches work well, including attention-free
         | SSMs.
        
         | lovasoa wrote:
         | How do you call the opposite of green washing? When you want to
         | show that you are burning as much energy on training models as
         | the others.
        
         | giancarlostoro wrote:
         | No idea, but can I be signed up for R&D jobs where you don't
         | necessarily build something generating revenue?
         | 
         | Maybe these are just projects they use to test and polish their
         | AI chips? Not sure.
        
         | shpongled wrote:
         | Probably because ByteDance and Facebook (spun out into
         | EvolutionaryScale) are doing it
        
         | robotresearcher wrote:
         | Apple has an ML research group. They do a mixture of obviously-
         | Apple things, other applications, generally useful
         | optimizations, and basic research.
         | 
         | https://machinelearning.apple.com/
        
         | bobmarleybiceps wrote:
         | This may not be the actual reason in this case, but I think
         | it's good to be aware of: A non-zero chunk of "ai for science"
         | research done at tech companies is basically done for
         | marketing. Even in cases where it's not directly beneficial for
         | the companies products or is unlikely to really lead to
         | anything substantial, it is still good for "prestige"
        
       | wild_pointer wrote:
       | Did you just assume what I think about protein folding
       | simplicity?!
        
       | IAmBroom wrote:
       | Link goes the github repository behind the article you might want
       | to read.
       | 
       | https://arxiv.org/abs/2509.18480
        
         | IAmBroom wrote:
         | And the abstract alone says (if I'm reading it correctly), "It
         | still takes AI; just not nearly as much as others are doing."
        
           | mentalgear wrote:
           | another form: transformers for the task
        
         | serjester wrote:
         | For those interested in the GitHub link.
         | 
         | https://github.com/apple/ml-simplefold
        
       | turblety wrote:
       | I wonder why Apple can create a model to fold proteins, but still
       | can't get Siri to control the phone competently? I'm not sure I
       | agree with Apple's priorities. I guess these things are not
       | synchronous and they can work on multiple things at a time.
        
         | tanelpoder wrote:
         | I guess it's because SimpleFold came from a research lab with
         | different autonomy and less competing interests and internal
         | politics...
        
         | frenchie4111 wrote:
         | I am genuinely interested where the strong negativity towards
         | Siri has come from in recent culture. From what I gather it's
         | likely due to the high expectations we have for Apple. But what
         | I don't really get is why is there not a similar amount of
         | negativity being directed at Google or Samsung, who both have
         | equally shit phone AI assistants (obviously this is just from
         | my perspective, I am a daily user of both iOS and a Samsung
         | Android)
         | 
         | I am not trying to defend Apple or Siri by any means. I think
         | the product absolutely should (and will) improve. I am just
         | curious to explore why there is such negativity being directed
         | specifically at Apple's AI assistant.
        
           | Invictus0 wrote:
           | For the last three iOS major versions, Siri has been unable
           | to execute the simple command "shuffle the playlist 'Jams'",
           | or any variation, like "play the playlist Jams on shuffle". I
           | am upset for that reason.
        
           | samuelg123 wrote:
           | I think Siri has always been criticized, likely because it
           | has never worked super well and it has the most eyes (or
           | ears) on it (iPhones still have 50% market share in the US).
           | 
           | And now that we have ChatGPT with voice mode, Gemini Live,
           | etc which have incredible speech recognition and reasoning
           | comparatively, it's harder to argue that "every voice
           | assistant is bad" still.
        
           | xp84 wrote:
           | As a vocal critic of Siri, I can give you a number of reasons
           | we hate it:
           | 
           | 1. It seems to be actively getting worse. On a daily basis, I
           | see it responding to queries nonsensically, like when i say
           | "play (song) by (artist)" (I have Apple Music) by opening my
           | Sirius app and putting on a random thing that isn't even that
           | artist. Other trivial commands are frequently just met with
           | apologies or searching the web.
           | 
           | 2. Over a year ago Apple conducted a flashy announcement full
           | of promises about how Siri would not only do the things that
           | it's been marketed as being able to do for the last decade,
           | but also things that no one has seen an assistant do. Many
           | people believe that announcement was based on fantasy
           | thinking and those people are looking more and more correct
           | every day that Apple ships no actual improvements to Siri.
           | 
           | 3. Apple also shipped a visual overhaul of how Siri looks,
           | which gives the impression that work has been done, leading
           | people to be even more disappointed when Siri continues to be
           | a pile of trash.
           | 
           | 4. The only competitor that makes sense to compare is Google,
           | since no one else has access to do useful things on your
           | device with your data. At least Google has a clear path to an
           | LLM-based assistant, since they've built an LLM. It seems
           | believable that android users will have access to a Gemini-
           | based assistant, whereas it appears to most of us that
           | Apple's internal dysfunction has rendered them unable to ship
           | something of that caliber.
        
           | citizenpaul wrote:
           | Is it just my rosie glasses or did siri work much better in
           | the first couple of years and seem to decline continually
           | since then. I actually used it a lot initially then
           | eventually disabled it as it never worked anymore.
        
             | devmor wrote:
             | I feel like the same is true of a lot of products that
             | moved from being programmatically connected ML workflows to
             | multi-modal AI.
             | 
             | We, the consumer, have received inferior products because
             | of the vague promise that the company might one day be able
             | to make it cheaper if they invest now.
        
           | SoftTalker wrote:
           | I've disabled Siri as much as I possibly can. I've never even
           | tried to use it. I would do the same for any other AI
           | assistant. I don't like that they are always listening, and I
           | just don't like talking to computers. I find it unnatural,
           | and I get irrationally angry when they don't understand what
           | I want.
           | 
           | If I could buy a phone without an assistant I would see that
           | as a desirable feature.
        
         | al_borland wrote:
         | Something like this doesn't actually have to work. There were
         | no expectations at all in this space.
         | 
         | Meanwhile, people expect perfection from Siri. At this point a
         | new version of Siri will never live up to people's
         | expectations. Had they released something on-par with ChatGPT,
         | people would hate it and probably file a class action lawsuit
         | against Apple over it.
         | 
         | The entire company isn't going to work on Siri. In a large
         | company there are a lot of priorities, and some things that
         | happen on the side as well. For all we know this was one
         | person's weekend project to help learn something new that will
         | later be applied to the priorities.
         | 
         | I've made plenty of hobby projects related to work that weren't
         | important or priorities, but what I learned along the want
         | proved extremely valuable to key deliverables down the road.
        
         | mapmeld wrote:
         | As I understand it, Siri and Alexa could be plugged into an
         | LLM, but changing it to an "open world" device that can tell
         | your kid something disturbing, text all of your contacts, buy
         | groceries, etc. comes with serious risk of reputational harm.
         | While still falling short of people's expectations if it isn't
         | ChatGPT-quality. OpenAI is new enough that they get to play by
         | different rules.
        
         | EasyMark wrote:
         | Fair point, even X was able to pump out a usable AI, grok.
        
       | stephenpontes wrote:
       | I remember first hearing about protein folding with the Folding
       | @Home project (https://foldingathome.org) back when I had a spare
       | media server and energy was cheap (free) in my college dorm. I'm
       | not knowledgable on this, but have we come a long way in terms of
       | making protein folding simpler on today's hardware, or is this
       | only applicable to certain types of problems?
       | 
       | It seems like the Folding @Home project is still around!
        
         | nkjoep wrote:
         | Team F@H forever!
        
         | _joel wrote:
         | Yep, that and SETI@Home. I loved the eye candy, even if I
         | didn't know what it fully meant.
        
           | seydor wrote:
           | How come we don't have AI@Home
        
             | throwup238 wrote:
             | The network bandwidth between nodes is a bigger limitation
             | than compute. The newest Nvidia cards come with 400gbit
             | busses now to communicate between them, even on a single
             | motherboard.
             | 
             | Compared to SETI or Folding @Home, this would work
             | _glacially_ slow for AI models.
        
               | fourthark wrote:
               | Seems like training would be a better match, where you
               | need tons of compute but don't care about latency.
        
           | gregsadetsky wrote:
           | That and project RC5 from the same time period..! :-)
           | 
           | https://www.distributed.net/RC5
           | 
           | https://en.wikipedia.org/wiki/RSA_Secret-Key_Challenge
           | 
           | I wonder what kind of performance would I get on a M1
           | computer today... haha
           | 
           | EDIT: people are still participating in rc5-72...??
           | https://stats.distributed.net/projects.php?project_id=8
        
         | roughly wrote:
         | As I understand it, folding at home was a physics based
         | simulation solver, whereas alphafold and its progeny (including
         | this) are statistical methods. The statistical methods are
         | much, much cheaper computationally, but rely on existing
         | protein folds and can't generate strong predictions for
         | proteins that don't have some similarities to proteins in their
         | training set.
         | 
         | In other words, it's a different approach that trades off
         | versatility for speed, but that trade off is significant enough
         | to make it viable to generate protein folds for really any
         | protein you're interested in - it moves folding from something
         | that's almost computationally infeasible for most projects to
         | something that you can just do for any protein as part of a
         | normal workflow.
        
         | ge96 wrote:
         | I contributed a lot on there too used my 3080Ti-FE as a small
         | heater in the winter
        
           | EasyMark wrote:
           | lol I still run it in the winter but I feel bad running it in
           | the summer, so I don't run it when A/C or heating is not
           | necessary. I figure some contribution is infinitely more than
           | 0 contribution.
        
         | EasyMark wrote:
         | They're still going and have made some great discoveries over
         | the years.
         | 
         | https://foldingathome.org/papers-results/?lng=en
        
         | jffry wrote:
         | Apparently from a F@H blog post [1] they say it's still useful
         | to know the dynamics of how it folded, in addition to the final
         | folded shape. And that having ML-folded proteins is a rich
         | target for simulation to validate and to understand how the
         | protein works
         | 
         | [1] https://foldingathome.org/2024/05/02/alphafold-opens-new-
         | opp...
        
       | foodevl wrote:
       | I was curious what the protein picture was showing: "Figure 1
       | Example predictions of SimpleFold on targets ... with ground
       | truth shown in light aqua and prediction in deep teal."
       | 
       | and now I'm even more curious why they thought "light aqua" vs
       | "deep teal" would be a good choice
        
         | gilleain wrote:
         | Well, figure a) shows a ribbon representation of the fold (as
         | helices and strands) of the protein 7QSW
         | (https://www.ebi.ac.uk/pdbe/entry/pdb/7qsw) which is RubisCO
         | (https://en.wikipedia.org/wiki/RuBisCO), an plant protein that
         | plays a key role in photosynthesis.
         | 
         | The different colours are for the predicted and 'real' (ground
         | truth) models. The fact that it is hard to distinguish is
         | partly the - as you point out - weird colour choice, but also
         | because they are so close together. An inaccurate prediction
         | would have parts that stand out more as they would not align
         | well in 3D space.
        
       | underdeserver wrote:
       | So, how does this compare to AlphaFold?
        
         | mentalgear wrote:
         | seems like they use the normal transformer architecture versus
         | deep fold's more specialised machine-learning approaches.
        
       | Invictus0 wrote:
       | They'll do anything but fix Siri
        
         | mentalgear wrote:
         | They can keep on doing stuff like this that's open-source and
         | beneficial to society.
        
       | frenchie4111 wrote:
       | I am curious to hear an expert weigh in on this approach's
       | implications for protein folding research. This sounds cool but
       | it's really unclear to me what the implications are
        
         | geremiiah wrote:
         | Their representation is simpler, just a transformer. That means
         | you can just plug in all the theory and tools that have been
         | developed specifically for transformers, most importantly you
         | can scale the model easier. But more than that, I think, it
         | shows that there was no magic to AlphaFold. The details of the
         | architecture and training method didn't matter much. All that
         | was needed was training a big enough model on a large enough
         | dataset. Indeed lots of people who have experimented with
         | AlphaFold have found it to behave similiar to LLMs, i.e. it
         | performs well on inputs close to the training dataset and but
         | it doesn't generalize well at all.
        
           | visarga wrote:
           | > But more than that, I think, it shows that there was no
           | magic to AlphaFold. The details of the architecture and
           | training method didn't matter much. All that was needed was
           | training a big enough model on a large enough dataset.
           | 
           | People often like to say that we just need one more
           | algorithmic breakthrough or two for AGI. But in reality it's
           | the dataset and the environment based learning. Almost any
           | model would do if you collected the data. It's not in the
           | model, it's outside where we need to work on.
        
           | aDyslecticCrow wrote:
           | I think the sentiment that simplicity is good, is a false
           | conclusion. Simplicity is simply good scientific methodology.
           | 
           | Doing too many things at once makes methods hard to adopt and
           | makes conclusions harder to draw. So we try to find simple
           | methods that show measurable gain, so we can adapt it to
           | future approaches.
           | 
           | Its a cycle between complexity and simplicity. When a new
           | simple and scalable approach beats the previous state of art,
           | that just means we discovered a new local maxima hill to
           | climp up.
        
         | epistasis wrote:
         | It may be a change in future models, perhaps. Here's one
         | person's opinion:
         | 
         | https://genomely.substack.com/p/simplefold-and-the-future-of...
         | 
         | But as with anything in research, it will take months and years
         | to see what the actual implications are. Predictions of future
         | directions can only go so far!
        
       | 331c8c71 wrote:
       | It is for structure prediction, not folding (rolleyes).
        
         | jandom wrote:
         | Pssst they'll realise scientists hand out here too
        
       | barbazoo wrote:
       | No folding here. Proteins go on the hanger or in the drawer.
        
       | kazinator wrote:
       | I'm satisfied with with folding roast beef onto a sandwich, or
       | folding egg whites into batter. All the protein folding action I
       | could ever want.
        
       | vbarrielle wrote:
       | A paper that says: "our approach is simpler than the state of the
       | art". But also does not loudly say "our approach is significantly
       | behind the state of the art on all metrics". Not easy to get
       | published, but I guess putting it as a preprint with a big
       | company's name will help...
        
       | shpongled wrote:
       | It's not totally novel, but it's very cool to see the continued
       | simplification of protein folding models - AF2 -> AF3 was a
       | reduction in model architecture complexity, and this is a another
       | step in the direction of the bitter lesson.
        
         | hashta wrote:
         | I'm not sure AF3's performance would hold up if it hadn't been
         | trained on data from AF2 which itself bakes in a lot of
         | inductive bias like equivariance
        
       | nextworddev wrote:
       | In industry Google practically dominates this field
        
       | hashta wrote:
       | One caveat that's easy to miss: the "simple" model here didn't
       | just learn folding from raw experimental structures. Most of its
       | training data comes from AlphaFold-style predictions. Millions of
       | protein structures that were themselves generated by big MSA-
       | based and highly engineered models.
       | 
       | It's not like we can throw away all the inductive biases and MSA
       | machinery, someone upstream still had to build and run those
       | models to create the training corpus.
        
         | mapmeld wrote:
         | And AlphaFold was validated with experimental observation of
         | folded proteins using X-rays
        
         | godelski wrote:
         | Is this so unusual? Almost everything that is simple was once
         | considered complex. That's the thing about emergence, you have
         | to go through all the complexities _first_ to find the
         | generalized and simpler formulations. It should be obvious that
         | things in nature run off of relatively simple rulesets, but it
         | 's like looking at a Game of Life and trying to reverse
         | engineer those rules _AND_ the starting parameters. Anyone
         | telling you such a task is easy is full of themselves. But then
         | again, who seriously believes that P=NP?
        
           | hashta wrote:
           | To people outside the field, the title/abstract can make it
           | sound like folding is just inherently simple now, but this
           | model wouldn't exist without the large synthetic dataset
           | produced by the more complex AF. The "simple" architecture is
           | still using the complex model indirectly through
           | distillation. We didn't really extract new tricks to design a
           | simpler model from scratch, we shifted the complexity from
           | the model space into the data space (think GPT-5 =>
           | GPT-5-mini, there's no GPT-5-mini without GPT-5)
        
             | stavros wrote:
             | But this is just a detail, right? If we went and
             | painstakingly catalogued millions of proteins, we'd be able
             | to use the simple model without needing a complex model to
             | generated data, no?
        
         | aDyslecticCrow wrote:
         | What i take away is the simplicity and scaling behavior. The ML
         | field often sees an increase in module complexity to reach
         | higher scores, and then a breakthrough where a simple model
         | performs on-par with the most complex. That such a "simple"
         | architecture works this well on its own, means we can
         | potentially add back the complexity again to reach further. Can
         | we add back MSA now? where will that take us?
         | 
         | My rough understanding of field is that a "rough" generative
         | model makes a bunch of decent guesses, and more formal
         | "verifiers" ensure they abide by the laws of physics and
         | geometry. The AI reduce the unfathomably large search-space so
         | the expensive simulation doesn't need to do so much wasted work
         | on dead-ends. If the guessing network improves, then the whole
         | process speeds up.
         | 
         | - I'm recalling the increasingly complex transfer functions in
         | redcurrant networks,
         | 
         | - The deep pre-processing chains before skip forward layers.
         | 
         | - The complex normalization objectives before Relu.
         | 
         | - The convoluted multi-objective GAN networks before diffusion.
         | 
         | - The complex multi-pass models before full-convolution
         | networks.
         | 
         | So basically, i'm very excited by this. Not because this itself
         | is an optimal architecture, but precisely because it isn't!
        
           | nextos wrote:
           | > Can we add back MSA now?
           | 
           | Using MSAs might be a local optimum. ESM showed good
           | performance on some protein problems without MSAs. MSAs offer
           | a nice inductive bias and better average performance.
           | However, the cost is doing poorly on proteins where MSAs are
           | not accurate. These include B and T cell receptors, which are
           | clinically very relevant.
           | 
           | Isomorphic Labs, Oxford, MRC, and others have started the
           | OpenBind Consortium (https://openbind.uk) to generate large-
           | scale structure and affinity data. I believe that once more
           | data is available, MSAs will be less relevant as model
           | inputs. They are "too linear".
        
       | dyauspitr wrote:
       | Isn't this a largely solved problem after Alphafold?
        
         | samfriedman wrote:
         | Maybe they've been working on it, but got scooped?
        
           | zamadatix wrote:
           | I don't think that's the case. The numbers in the paper
           | suggest ~92% of the training data comes from pre-existing AI
           | models, including AlphaFold, and they claim things like:
           | 
           | > We largely adopt the data pipeline implemented in Boltz-11
           | 1https://github.com/jwohlwend/boltz (Wohlwend et al., 2024),
           | which is an open-source replication of AlphaFold3
           | 
           | I believe the story here is largely that they simplified the
           | architecture and scaled it to 3B parameters while maintaining
           | leading results.
        
       | phoenicyan wrote:
       | Curious since AlphaFold got released: have classical molecular
       | dynamics sims in this area become obsolete, at least for protein
       | folding? How does the research coming out of venues like DESRES
       | compare? Are they working on more specific problems in the same
       | area or are they in a different business altogether?
        
         | the__alchemist wrote:
         | No. AlphaFold doesn't do dynamics; it does end-state snapshots
         | only. It does not do anything about the motion of the atoms,
         | which is the core functionality of MD.
        
         | tripplyons wrote:
         | I was curious about what was released, and the parameters for
         | AlphaFold V3 are only given to certain groups for non-
         | commercial use: https://github.com/google-
         | deepmind/alphafold3?tab=readme-ov-...
         | 
         | However, it seems like anyone can download the parameters for
         | AlphaFold V2: https://github.com/google-
         | deepmind/alphafold?tab=readme-ov-f...
        
         | dekhn wrote:
         | MD was never really a viable way to do structure prediction, so
         | it didn't become obsolete with AlphaFold. Instead, MD is more
         | useful for studying the physical process of protein folding
         | (before the protein folds to its final structure, as well as
         | once it has reached its final structure and sort of jiggles and
         | wiggles around that).
        
       | ziofill wrote:
       | In the plots in Fig. 4 it looks like they should have continued
       | the training because the performance was still climbing, am I
       | reading it incorrectly?
        
       | GistNoesis wrote:
       | Intellectually, I don't like this approach.
       | 
       | Predicting the end-result from the sequence of protein directly
       | is prone to miss any new phenomenon and would just
       | regurgitate/interpolate the training datasets.
       | 
       | I would much prefer an approach based on first principles.
       | 
       | In theory folding is easy, it's just running a simulation of your
       | protein surrounded by some water molecules for the same number of
       | nano-seconds nature do.
       | 
       | The problem is that usually this take a long time because
       | evolving a system needs to compute the energy of the system as a
       | position of the atoms which is a complex problem involving
       | Quantum Mechanics. It's mostly due to the behavior of the
       | electrons, but because they are much lighter they operate on a
       | faster timescale. You typically don't care about them, only the
       | effect they have on your atoms.
       | 
       | In the past, you would use various Lennard-Jones potentials for
       | pairs of atoms when the pair of atoms are unbounded, and other
       | potentials when they are bonded and it would get very complex
       | very quickly. But now there are deep-learning based approach to
       | compute the energy of the system by using a neural network. (See
       | (Gromacs) Neural Network Potentials
       | https://rowansci.com/publications/introduction-to-nnps ). So you
       | train these networks so that they learn the local interactions
       | between atoms based on trajectories generated from ab-initio
       | theories. This allows you to have a faster simulator which
       | approximate the more complex physics. It's in a sort just
       | tabulating using a neural network the effect of the electrons
       | would have in a specific atom arrangements according to the
       | theory you have chosen.
       | 
       | At any time if you have some doubt, you can always run the slower
       | simulator in the small local neighborhood to check that the
       | effective field neural network approximation holds.
       | 
       | Only then once you have your simulator which is able to fold, you
       | can generate some dataset of pairs "sequence of protein" to "end
       | of trajectory", to learn the shortcut like Alpha/Simple/Fold do.
       | And when in doubt you can go back to the slower more precise
       | method.
       | 
       | If you had enough data and can train perfectly a model with
       | sufficient representation power, you could theoretically infer
       | the correct physics just from the correspondence initial to final
       | arrangements. But if you don't have enough data it will just
       | learn some shortcut and accept that it will be wrong some times.
        
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