How our cells (nearly) perfected making nanobots The protein folding problem

How our cells (nearly) perfected making nanobots NanoRooms 53.8K subscribers Subscribe 2.3K Share Download Thanks Clip 49,795 views Jun 30, 2024 To try everything Brilliant has to offer—free—for a full 30 days, visit https://brilliant.org/NanoRooms . You’ll also get 20% off an annual premium subscription. My Patreon: patreon.com/NanoRooms Books & Papers: Protein folding in tunnel https://pubmed.ncbi.nlm.nih.gov/28556... another paper with a folded protein in tunnel: https://www.cell.com/cell-reports/ful... other references can be found here: https://www.mdpi.com/2218-273X/10/1/9... one last example: https://www.rcsb.org/structure/5NP6 Hsp40’s buffering capacity: https://scholar.google.ca/citations?v... CFTR drugs: https://www.science.org/doi/10.1126/s... Transcript Search in video 0:00 proteins are little Nanobots that do all 0:02 sorts of things inside of your cells 0:05 they carry signals copy DNA ensure your 0:08 arms grow where they're supposed to and 0:11 much more the blueprint for these 0:13 complex 3D Nanobots are conveniently 0:16 stored in the DNA using a very clever 0:19 system three letters of DNA encode what 0:21 flavor of amino acid will be added to 0:24 the protein and the properties of these 0:27 amino acids dictate what shape and 0:30 function the protein will take on it's 0:32 simple clever and elegant the only 0:35 problem is there are countless ways in 0:38 which this can go wrong the consequences 0:41 of being wrong cystic fibrosis the mad 0:44 cow disease and all sorts of 0:46 neurodegenerative disorders all diseases 0:49 that have a heavy impact on the 0:52 livelihoods of the 0:54 victims this is the science behind a 0:58 clever Machinery of protein 1:02 folding how does a given blueprint know 1:05 how to assemble itself the answer to 1:07 that is forces these forces are encoded 1:11 within the flavor of amino acid within 1:14 the side chain specifically charges 1:17 polarity the hydrophobic Vander wals the 1:20 quantum mechanical calent bonds and so 1:22 on these side chains with different 1:25 forces interact with one another to form 1:27 a 3D structure the inter interactions 1:30 aren't limited within the Shan basically 1:33 anything that can have a mechanical 1:35 impact will have a mechanical impact on 1:38 the protein the polar watery environment 1:41 of the cells drives everything 1:42 hydrophobic inside other proteins 1:45 surrounding it can give interesting 1:47 forces that change the shape of the 1:49 protein the temperature can make things 1:51 more shaky and so much more take a look 1:54 at these two sequences of protein 1:56 there's only one difference in the 1:58 letters one has glutamine and one has 2:01 lysine and it's the subtle difference 2:04 that turns normal red blood cells into 2:07 CLE cell 2:08 disease the way proteins fold can be 2:11 represented by the energy funnel the 2:13 lower the energy the more stable the 2:16 structure is but sometimes though the 2:18 protein can get stuck in one of these 2:21 little Wells that aren't as deep but 2:23 they require a bit of a boost to get out 2:25 of and other times they're going in a 2:27 completely wrong direction and become 2:29 nasty misfolded messes that can lead to 2:32 diseases the biggest problem is when a 2:34 protein is unfolded its protein sequence 2:37 can adopt over 10 to the 30 different 2:40 confirmations and would take millions of 2:42 years for the protein to search until it 2:45 finds the right one because ultimately 2:47 there is only one correct 3D structure 2:50 for a given protein but if there are 2:54 that many ways to go wrong then why 2:56 aren't we all sick why are all of our 2:59 proteins ready for for production even 3:00 though on paper it would take millions 3:02 of years to find the right shape how 3:05 does the cell help the protein fold 3:08 properly but how do scientists come up 3:11 with these numbers from Life 3:12 science-based phenomena luckily the 3:14 sponsor of today's video brilliant.org 3:16 has a unique and Powerful way to help 3:19 you get started on that brilliant is 3:21 where you can learn by doing with 3:23 thousands of interactive lessons in math 3:25 data analysis programming and AI the 3:28 interactives um brilliant help you build 3:30 your critical thinking skills through 3:32 problem solving not just memorization 3:35 which will help you own the knowledge 3:36 you've obtained so while you're building 3:39 real knowledge on specific topics you'll 3:42 also become a better thinker Brant 3:44 recently launched a ton of new content 3:46 in data if you want to deeply understand 3:49 science and come up with the conclusions 3:51 found in this video learning data 3:53 science will be a great start especially 3:55 when you want to understand the 3:56 algorithms behind protein folding 3:58 related AI such as Alpha fold these 4:01 courses are perfect for Learners of any 4:03 level to start or continue learning data 4:05 analysis with a fully built out suit of 4:08 new content from base theorem to 4:10 multiple linear regressions you'll also 4:12 learn how to parse and visualize massive 4:15 data sets to make them easier to 4:16 interpret beyond that you'll also Gain 4:19 real world Insight by working with real 4:21 data sets from sources such as Starbucks 4:24 X Spotify and more to try everything 4:28 brilliant has to offer for free for a 4:30 full 30 days visit brilliant.org nanor 4:33 rooms or click on the link in the 4:35 description below you'll also get 20% 4:37 off an annual premium subscription to 4:40 answer all of that we're going to have 4:42 to open up the hood of the cell and see 4:44 how it goes from DNA blueprints to 4:47 protein robots first the DNA gets 4:50 transcribed into RNA then RNA gets 4:53 translated into proteins using ribosomes 4:56 every three letters of RNA gets read 4:59 into one amino acid and they are then 5:02 linked together to form a protein chain 5:05 the essence of getting it to fold into 5:07 the right shape is to restrict the 5:10 possibilities of folding in fact you're 5:13 about to see it happen right now in this 5:15 animation as the protein is getting 5:18 synthesized it has to go through a tube 5:20 in the ribosome the tube itself prevents 5:23 the small chain of amino acids from 5:26 exploring all the possible confirmations 5:29 and by doing so it forces the small 5:31 chain to only explore a small number of 5:34 shapes which can in some cases allow the 5:37 formation of alpha helices restricting 5:40 the number of possibilities is the major 5:42 driver behind the folding funnel but the 5:46 tube is too narrow to allow a protein to 5:48 adopt a more complex structure and 5:50 eventually the protein has to exit the 5:53 tube when it gets longer but that is 5:56 only the beginning the cells can 5:58 actually do much more beyond 6:01 that in fact these mechanisms were 6:05 actually discovered 6:06 accidentally so the heat shock response 6:08 was discovered a little bit by chance 6:11 scientists were studying the fruit 6:13 flight which a tiny little flight using 6:16 different incubators and by mistake they 6:19 set some of these incubator at a higher 6:21 temperature and when they were 6:22 incubating the fly at the higher 6:24 temperature what they realized is that 6:26 they were turning on a transcription 6:28 response the heat shock response 6:29 response where many genes now were 6:31 specifically transcribed only at the 6:34 elevated temperature and later on when 6:36 we studied the function of these genes 6:38 what we discover is that they were 6:40 encoding sharen proteins that were there 6:42 in the cells to help increasing the 6:45 folding capacities when the temperature 6:47 was 6:48 increased in hindsight this is a pretty 6:51 logical place to find things that help 6:53 proteins fold if you recall temperature 6:56 can make things a lot more shaky and can 6:58 disrupt the protein Str structure so the 7:00 cell has to send all these First 7:02 Responders to do damage control these 7:05 chapon functions all have one thing in 7:07 common they lead to restricting the 7:10 possible shapes of the protein when they 7:12 interact with their client here's a fun 7:15 example a protein is for sure misfolded 7:18 if the hydrophobic sides are exposed in 7:20 a Cell composed of mostly water the HSP 7:24 40 chapone detects these and brings it 7:27 to 7:28 hsp70 HSP p70 then holds on to one of 7:31 these hydrophobic regions let's say this 7:34 protein has three hydrophobic regions 7:37 all three would be able to interact with 7:39 one another but if we have hsp70 bound 7:42 on a then only B and C can interact 7:46 followed by a after its release in fact 7:49 one of Dr mayor's research found another 7:51 function of HSP 40 so in many genetic 7:54 disease one of the issue can be that a 7:58 single mutations 8:00 uh can induce a bit of misfolding so 8:02 this is our what we call the wild type 8:04 proteins it has all its 8:07 sequence and then here we have a mutant 8:10 proteins that just have one little 8:12 change now that little change is going 8:15 to change the shape of our proteins so 8:17 normally the cells can recognize that 8:20 and what it will do it would simply 8:22 degrade that misfolded proteins thanks 8:25 to the ubiqutin pisone 8:28 system now sha pron uh that normally 8:31 functions in helping the folding of 8:34 these uh 8:36 proteins can also have additional 8:38 function in the cells and they can be 8:40 used as buffering agent so one of the 8:43 shaon that we study D 8:47 aj2 what it does it actually put a break 8:50 and it prevents that fast degradation on 8:53 the cells by helping the misfolded 8:56 proteins to try to go back to its normal 8:59 shape even cooler still the cell can 9:02 literally put the misfolded proteins in 9:04 jail known as the trick Cho pronin 9:07 complex and force it to fold again in 9:10 the proper environment talk about a 9:12 correctional facility don't you think if 9:15 all else fails the proteins are tagged 9:17 using ubiquitin and guided to a literal 9:20 protein Shredder the danger of wrong 9:22 protein shape really is that extreme but 9:25 it Becks the question if the system 9:28 works as well as I have said why do 9:30 protein folding diseases still happen 9:33 well as you grow older your cells can 9:35 start to accumulate more and more 9:37 mutations and simply make more errors 9:39 when making proteins that can also amass 9:41 more damages such as oxidation these 9:44 mutations can get to the point where 9:46 ubiqutin and chaon can't fix them 9:49 anymore getting older also has some 9:51 unexplained side effects your cells will 9:54 make fewer and fewer chapon thus leaving 9:56 you with a lower capacity to fold 9:58 proteins these misfolded proteins can do 10:01 worse than just having the wrong 10:03 function in fact they can latch onto 10:05 normal proteins and corrupt them into 10:07 misfolded proteins in fact this 10:09 proliferation mechanism can be seen in 10:11 diseases such as the mad cow 10:13 disease these are so severe that cells 10:17 have one of two ways to deal with it 10:19 they can either degrade the ABD 10:21 completely or if they're not recognized 10:23 they will just aggregate so the cell can 10:25 just lump these together but sometimes 10:28 these mechanisms work all too well so we 10:32 have the opposite issue sometimes we 10:34 degrade too many proteins this is how we 10:37 have diseases such as cystic 10:39 fibrosis it affects the pumps on the 10:41 surface of cells that secrete liquids 10:44 such as mucus and digestive juices by 10:46 means of mutations or just plainly bad 10:48 protein folding the pump that pumps 10:51 water out gets sent to immediate 10:53 degradation but without these pumps at 10:55 all the water of the liquids that are 10:58 supposed to lubricate these tubes 11:00 thicken up in fact it can get so thick 11:02 that it plugs all of these important 11:06 tubes so now there's hope uh for people 11:09 that have cystic fibrosis there are 11:11 drugs that can have a similar functions 11:14 than a chapron proteins we are calling 11:16 them correctors and so they help the 11:19 proteins to go back to their normal 11:21 shape so that they're not rapidly 11:23 degraded by the cells similar to the 11:25 buffering effect that I was talking 11:27 earlier and so now by adding that drug 11:30 adding the corrector drugs there's 11:33 enough of the cftr the proteins that is 11:37 affected in cystic fibrosis that can be 11:39 expressed in the cell surface and pump 11:42 the water uh adequately allowing now the 11:45 patients to have a more normal life as 11:48 you can see protein folding is a highly 11:50 important process that can be the 11:52 difference between a functioning 11:54 Workforce of the cell and a destructive 11:56 disease but how do we know what sequence 11:59 of protein corresponds to what structure 12:02 next time we'll be delving into how 12:04 alpha fold works and the story of the 12:06 uncredited inventor behind one of the 12:09 most important algorithms that 12:10 kickstarted Alpha fold stay tuned And 12:16 subscribe special thanks to Professor 12:18 mayor for helping and scripting the 12:20 creation of this video all of his works 12:22 and others referencing the video are in 12:24 the description for behind the scenes 12:27 please check out my patreon links below 12:29 see you soon Music used in intro: • Epic Heroic Trailer by Infraction [No... Animated using molecular nodes by ‪@BradyJohnston‬ https://bradyajohnston.github.io/Mole... Transcript Follow along using the transcript. Show transcript NanoRooms 53.8K subscribers Videos About 126 Comments rongmaw lin Add a comment... Pinned by NanoRooms @Nanorooms 1 month ago To try everything Brilliant has to offer—free—for a full 30 days, visit https://brilliant.org/NanoRooms. You’ll also get 20% off an annual premium subscription. 7 Reply 1 reply @enestaylan118 1 month ago This is just a correction for sickle cell disease: the mutation is on the 6th amino acid of the beta chain of hemoglobin, which causes glutamic acid to be replaced by valine, not lysine. 97 Reply 3 replies @peterwhite8424 1 month ago Lego bricks arranged themselves more or less random and somehow our consciousness pops out in it 6 Reply @br3nto 1 month ago Wow. It really does seem like a 3D version of a Turing machine at multiple scales. First at the DNA scale, then at the protein chain scale with the alphabet being the different forces. That’s pretty cool. Then at the level of the completed proteins, etc etc etc. 7 Reply 1 reply @tcaDNAp 1 month ago Prof. Thibault Mayor has the coolest vibe and great production in this video 4 Reply @ShauryaAlapati 1 month ago ive been waiting for these to come out 8 Reply @Witcheridoo 1 month ago Your visuals always amaze me 6 Reply @kacemtoubal3580 1 month ago Hello everyone, It's been a long time since I've been on NanoRooms, I hope you are doing well, and I really hope to reveal the mystery of my question: How do our cells know that a specific protein has mutated? I appreciate your effort and time in making those videos, it is magnificent work. Thanks for everything! 12 Reply 1 reply @alsund1866 2 weeks ago I always thought that proteins each had only one way to fold but now hearing that they can accidently fold in so many other ways is really eye opening Reply @grygoriyzolotarov3228 1 month ago I love your channel 4 Reply @ramanShariati 1 month ago quality is LEGENDARY 1 Reply @jpphoton 1 month ago Excellent presentation and synopsis - clear and no fluff. Tanks Reply @mrjesuschrist2u 1 month ago 10^30 possibility only takes millions of years? If you tried a new fold every second for 10^30 tries.....The protein folding problem is very interesting when it comes to origins of life on earth, time is a huge hurdle. For every 1 properly folded protein there are 10^77 non-functional(axe, 2010). Without DNA/RNA the possibility of folding into a functional protein is even worse. The math is not friendly if you appreciate the magnitude of the numbers. 16 Reply 6 replies @AlanZucconi 1 month ago Thank you for making this, I really enjoyed it! Can I ask which software did you use to render and animate the proteins? 5 Reply @amelieschreiber6502 1 month ago (edited) At about 2:45 you mention that there is only one correct conformation for any given protein. There are about 1%-4% of proteins with multiple metastable conformations. These are called metamorphic proteins, or sometimes "fold-switchers". This is why AI models like Distributional Graphormer exist, to sample the Boltzmann distribution. 9 Reply @Clockworkbio 1 month ago $4.99 Such a sick setup for an AlphaFold video! Really excited to see what you’re building towards! Reply @charadremur333 1 month ago Finely another video! 25 minutes ago nonetheless. I would love a video on how some of these misfolded proteins cause others to misfold. 7 Reply @SlavTiger 2 weeks ago can you make a video talking about prp and dopple? 1 Reply @OzGoober 1 month ago Great work! 1 Reply @Dmadiroe 4 weeks ago Great video, thank you. Reply @cozumel5608 1 month ago oh thanks 3 Reply @jorgearango6108 4 weeks ago Extraordinary Reply @Ousmanedembele811Tbos 1 month ago This information makes me feel fragile. 1 Reply @noelbreitenbach8673 1 month ago This channel is very awesome Reply @gleb7186 1 month ago Do we know why some misfolded proteins causing other proteins to do the same (like in mad cow disease)? At least a theory? 3 Reply 1 reply @vinniepeterss 1 month ago top notch Reply @evgenigenev5958 7 days ago What program do you use to make these animations Reply @kaba1996 1 month ago Let's goo! 1 Reply @LPesi-eh3qi 1 month ago Great video! I really would want to know what kind of study you did to gain this knowlodge, im a software development student, i hope to hear from you Reply @bradhilton2283 3 weeks ago That is some very interesting stuff. Reply @Valgween 1 month ago 2:48 laughs in intrinsically disordered proteins. 1 Reply @MusingsFromTheJohn00 10 days ago The information for a human being or other multicellular animal is not only stored in the DNA. The DNA is one long term memory system within a cell but not the only one. One major point of this is that scientifically we know beyond a reasonable doubt that there is a swarm intelligence going on inside cells and between cells, but we only have a partial understanding of how this works and there are a number of aspects to it we completely do not know. On the other hand, we know enough to be able to see that it will be only a matter of time before we do fully understand this, whether it takes 10 years, 100 years, or a 1,000 years to gain such full understanding. Reply @AmruMagdy 1 month ago ارتبط صوت اللواء فايز الدويري بنصر السابع من أكتوبر ربنا لا يحرمنا من صوتك Reply @Khashayarissi-ob4yj 1 month ago With luck and more power of you. Reply @ultrasoft5555 1 month ago Would be worth to mention intrinsically disordered proteins 1 Reply @fnnnn5986 1 month ago Thank you DNA polymerase for keeping us alive Reply 1 reply @franciscomendoza754 1 month ago This is so cool, and so soooo interesting, but is too much for my little mind :c Reply @diabmourani9601 1 month ago that's so great i cannot wait until humanity will be able to defeat disease for ever Reply @No2AI 1 month ago Advanced Chemistry machines …. That is all we are . 1 Reply @Ascintony 1 month ago Hey I have a question. If the hydrophobic regions of the proteins are on the inside, then how do membrane proteins have a hydrophobic outer region enabling then to be inserted in the lipid bilayer? 2 Reply 5 replies @hobocraft0 1 month ago 1 Reply @vinniepeterss 1 month ago Reply @Jia-944 1 month ago just out of curiosity , type of protein (intrinsic disoriented proteins) does not have a specific shape, is it possible to predict its structure Reply @Jia-944 1 month ago Hi，I just want to say that your videos are soooooo amazing! I am a high school student from china, I have long been wondering if using fundamental formulas like physic!! I really hope more people could know about this amazing topic therefore I am wondering if i could get your permission to share your videos on a Chinese video platform Bilibili, so more people would be able to access this amazing topic!!! Reply @jinanren2026 1 month ago nanomachines son. 1 Reply @bataalexander9703 1 month ago (edited) If a protein is prone to misfolding, then perhaps its primary structure is not optimal, there has to be a better one. Reply @EdT.-xt6yv 1 month ago 2:30 Reply @vincentcleaver1925 1 month ago Statistics! Or, as chemistry students used to joke, sadistics! Reply @SB-nd4yv 1 month ago suberb! 1 Reply @htopherollem649 1 month ago better vid title suggestion "biological protein folding and what can go wrong " because of the prevalence of "clickbait titling " I nearly disregarded your video about a subject that I would love to know more about. 11 Reply 3 replies @empmachine 1 month ago Hydrophobic VDWs eh? Sure you aren't buzzwording a bit?? ;p Great video! Reply @sssssnake222 1 month ago Atomic dimensional life designed us. Reply @hamzacasdasdasd 1 month ago neture is the only think cleverly designed not by humans Reply @jdkingsley6543 1 month ago It blows my mind that we can study something like this but cant solve some of humanities other issues. Like poverty— just amazing b Reply @user-cu9ww9tj4i 1 month ago Westworld Reply @hamzaabu-zaid2596 3 weeks ago AAAAAAAAAAAAAAAAAAAAAAAAAUG Reply @IB4UUB4ME 3 weeks ago I’m sure that there won’t be any argue I g here over who is right and who is not, right people? ️️ Unfortunately they were perfect at one time, and will be again. Reply @gianpaulgraziosi6171 1 month ago It’s called the immune system. Reply 1 reply @tom-hy1kn 1 month ago But who made our cells? Reply 1 reply @123ghassan123 1 month ago Science is the 20th century Gods Last Messenger. 2 Reply @differentone_p 1 month ago good morning I hope you had a great day today love you too baby girl I love you too baby girl I love you too baby girl I love you too baby girl Reply @Duggleftforthemilk 1 month ago This is proof of the Lord's Design. 1 Reply 18 replies @Alpha_GameDev-wq5cc 1 month ago 8:28 Oh My God get this professor out of the video… he can’t F-ing use a marker without constantly creating that unbearable squeaky noise. Literally unwatchable, I had a physically painful experience… Jesus christ Reply