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Scientists create first billion-atom biomolecular simulation

lanl.gov

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Re: Scientists create first billion-atom biomolecular simulation

#21

Post by AllegedAlec »

throwaway_law wrote: post #11
AllegedAlec wrote: post #3

While very impressive, I'm not sure about their goal: > Modeling genes at the atomistic level is the first step toward creating a complete explanation of how DNA expands and contracts, which controls genetic on/off switching. That does not work in isolation like this: McGuffee and Elcock did some fantastic work in 2010 where they showed that protein stability is quite dependent on that the cytoplasm is insanely dense…

>And that is before I start on whether this is an actually useful way to research gene expression in general Haven't we already reproduced existing bacteria/DNA from atoms which has allowed us to more easily study gene expression? Moreover, we take a bacteria with 200 genes ( we understand a lot of the gene functions/expressions, but we don't understand what all these 200 genes do). Thus, we synthetically reproduce t…

> Haven't we already reproduced existing bacteria/DNA from atoms which has allowed us to more easily study gene expression?

I don't think so. I think they just took a small existing bacteria and by pruning its genome came to something which was minimally viable.

Re: Scientists create first billion-atom biomolecular simulation

#22

Post by AllegedAlec »

cjslep wrote: post #4
AllegedAlec wrote: post #3

While very impressive, I'm not sure about their goal: > Modeling genes at the atomistic level is the first step toward creating a complete explanation of how DNA expands and contracts, which controls genetic on/off switching. That does not work in isolation like this: McGuffee and Elcock did some fantastic work in 2010 where they showed that protein stability is quite dependent on that the cytoplasm is insanely dense…

Depending on how they model the simulation's fields, long range intra-atomic forces, and boundary conditions, I'd still say this kind of molecular dynamic simulation is better than doing nothing and waiting to simulate the whole nucleus. It could have accounted for these sorts of effects in a way that is cruder than whole nucleus simulation, but I haven't read any papers about this simulation.

I think that the entire enterprise is a red herring.

It's nigh-impossible to understand this system by working from the bottom up. I don't see what kind of insight you'd get from this that you wouldn't get from a more understandable simplification in a minute fraction of the time.

For example: yeah, if a gene is contained in densely packed nucleosomes it'll be harder to express. But knowing that is enough; the exact details of how that works atomically is not the issue here. There are much larger issues with gene expression we don't understand which can much more easily give us much more insight into the workings of the system.

Re: Scientists create first billion-atom biomolecular simulation

#23

Post by dekhn »

callesgg wrote: post #5

"130,000 processor cores with 1 ns/day" Still a bit to slow... I guess it is progress :)

when I wrote my thesis in 2001 I got 1ns/week on a much smaller system (1M atoms running on a T3E w/ ~256-512 processors).

It's not really clear whether MD simulations like this are true contributions or whether they will ever produce useful results compared to well-parameterized neural nets.

Re: Scientists create first billion-atom biomolecular simulation

#24

Post by dekhn »

jryb wrote: post #8

Biologist's perspective: this paper is not about the biology. The simulation performed here has zero biological interest - the point of the paper was to show how efficient and scalable their software is. This article about the paper is terrible, but honestly I feel like they should be given a pass - it's hard to justify to a lay audience that understands neither DNA nor memory bandwidth why you would choose to study…

I agree this paper isn't really useful for biology. LANL maintains team of pseudo-biologists who scale up MD simulations and publish papers like this periodically (https://www.lanl.gov/projects/karissa/Ribosomes.html shows some previous work).

I wish this was a field where you could just apply more CPU and get better results (I say that with multiple papers published under my name which claim exactly that) but I'm skeptical. The force fields we use are far too approximate (point charges, assumption of transferrability) and it really does seem like we don't actually need most of this information to answer the questions we want to answer- those can be answered using more parsimonious techniques.

Re: Scientists create first billion-atom biomolecular simulation

#25

Post by bocklund »

dekhn wrote: post #23
callesgg wrote: post #5

"130,000 processor cores with 1 ns/day" Still a bit to slow... I guess it is progress :)

when I wrote my thesis in 2001 I got 1ns/week on a much smaller system (1M atoms running on a T3E w/ ~256-512 processors). It's not really clear whether MD simulations like this are true contributions or whether they will ever produce useful results compared to well-parameterized neural nets.

Are NNs producing useful results in this area? I'm on the density functional theory side of things, so much smaller scales than MD.

To me, it's not clear whether we are good at quantifying when a neural net is well-parameterized in atomistic simulations.

The limitations of MD simulations and all the built in assumptions are well understood. We can reason about where our simulations might fail, even for very large systems. It's always a question about whether the underlying model can capture all the physics that occurs.

With a NN or other black box model, there's no way to reason about it except for benchmarking test/validation sets that (hopefully) capture the physics that you care about, but you still cannot really reason about how well the model will extrapolate to multiple interacting physics with different magnitudes at different length scales.

Re: Scientists create first billion-atom biomolecular simulation

#26

Post by dekhn »

stochastic_monk wrote: post #14
jryb wrote: post #8

Biologist's perspective: this paper is not about the biology. The simulation performed here has zero biological interest - the point of the paper was to show how efficient and scalable their software is. This article about the paper is terrible, but honestly I feel like they should be given a pass - it's hard to justify to a lay audience that understands neither DNA nor memory bandwidth why you would choose to study…

I'm not familiar with this method, but NAMD and CHARM are a great way to inspect biological systems at greater resolution than experimental methods can measure. There was really cool work on fibrinogen about a decade ago showing how it provides elasticity. Reference: https://www.ks.uiuc.edu/Highlights/?section=2008&highlight=2...

That's a PR narrative twisted to make the results sound much more useful than they really were :(

Re: Scientists create first billion-atom biomolecular simulation

#27

Post by dekhn »

bocklund wrote: post #25
dekhn wrote: post #23

Earlier quoted context omitted.

when I wrote my thesis in 2001 I got 1ns/week on a much smaller system (1M atoms running on a T3E w/ ~256-512 processors). It's not really clear whether MD simulations like this are true contributions or whether they will ever produce useful results compared to well-parameterized neural nets.

Are NNs producing useful results in this area? I'm on the density functional theory side of things, so much smaller scales than MD. To me, it's not clear whether we are good at quantifying when a neural net is well-parameterized in atomistic simulations. The limitations of MD simulations and all the built in assumptions are well understood. We can reason about where our simulations might fail, even for very large sys…

I don't think anybody has shown that NNs produce better predictions of protein models (yet).

The limitations of MD aren't well understood. We don't know the implications of using a polarizable water model other than to say "it should be more accurate".

All the statements you make about NNs apply to MDs since MDs are basically feedforward ASTs with the same level of complexity and non-linearity as NNs.

Re: Scientists create first billion-atom biomolecular simulation

#28

Post by phkahler »

thatcat wrote: post #20
phkahler wrote: post #15

Earlier quoted context omitted.

Maybe the problem is that these scientists aren't doing science, they did some engineering. That's great, but it doesnt fit their publishing model.

What is the engineer publishing model?

One engineering model is to put the code on github under an open source license so people can use it. But please dont just put it out there and walk away. If you want to develop a useful piece of software, find a way to maintain it.

Another model is to offer it for sale as a product. Either way, engineers dont really care about publishing, we care about making useful things and Shari g how-to.

Re: Scientists create first billion-atom biomolecular simulation

#29

Post by throwaway_law »

AllegedAlec wrote: post #21
throwaway_law wrote: post #11

Earlier quoted context omitted.

>And that is before I start on whether this is an actually useful way to research gene expression in general Haven't we already reproduced existing bacteria/DNA from atoms which has allowed us to more easily study gene expression? Moreover, we take a bacteria with 200 genes ( we understand a lot of the gene functions/expressions, but we don't understand what all these 200 genes do). Thus, we synthetically reproduce t…

> Haven't we already reproduced existing bacteria/DNA from atoms which has allowed us to more easily study gene expression? I don't think so. I think they just took a small existing bacteria and by pruning its genome came to something which was minimally viable.

>pruning its genome came to something which was minimally viable

That sounds something like CRISPR or gene modification of an existing organism genome, maybe even taking genes from one species and inserting them into another (taking bioluminescent jelly fish and putting certain genes into cats or plants to make them glow). But, I'm talking about more recent successes of actually reproducing the DNA (synthetic DNA) from the atomic level up not modifying existing "natural DNA".

Sorry, I don't have enough time to search for recent studies, but here is old article about first "synthetic DNA" we created and inserted into cells that took off and self-replicated back in 2008: https://www.wired.com/2010/05/scientists-create-first-self-r...

The link seems to reference the first success of fully synthetic DNA, but I have recently been listening to podcasts about more recent experiemnts/studies, specifically reproducing bacteria with full synthetic DNA (which is stripped down as much as possible to maintain viability) for the purpose of studying gene expression and hopefully begin to identify what the currently unknown genes sequences do.

Re: Scientists create first billion-atom biomolecular simulation

#30

Post by dekhn »

AllegedAlec wrote: post #3

While very impressive, I'm not sure about their goal: > Modeling genes at the atomistic level is the first step toward creating a complete explanation of how DNA expands and contracts, which controls genetic on/off switching. That does not work in isolation like this: McGuffee and Elcock did some fantastic work in 2010 where they showed that protein stability is quite dependent on that the cytoplasm is insanely dense…

you can get 95% of the effects of macromolecular crowding by just shoving PEG into the system (the very first paper we covered in grad school showed that proteins in packed cells have elevated kinetic rates and free enegry of ATP hydrolysis isn't the value measured at STP, by using PEG as a proxy).

If I were to attempt to do gene regulation studies by MD (I share your skepticism!) I would just put a bunch of PEG in as a water replacement.

In fact that's a paper right there- "Effect of increasing macromolecular crowding on the accuracy of DNA simulations for regulation prediction" :)

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