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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 them to be inserted in the lipid bilayer?
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.
2:36 Wish you spent more time talking about the funnel shaped energy landscape, which is the true MVP in protein folding. Cyrus Levinthal once estimated that a protein has 10^300 different conformations, and that it would take MANY times longer than the AGE OF THE UNIVERSE to fold into the native state... but this ONLY holds true if we assume a FLAT energy landscape (such as for intrinsically disordered proteins). A funnel shaped landscape ensures that regardless of the starting conformation, unfolded proteins (almost) always fold into the correct conformation in a timely manner, just like how a ball rolls down a hill. The other things you mentioned (ribosome, chaperones, ubiquitin proteasome system) are indeed important, but the energy landscape comes first
yoo clockwork! I'm only on this video because your plant series kick-started an interest in molecular biochemistry. thank you for your efforts and I'm so excited for the rest of season 2!
@@danielnoon4032 really glad my videos catalyzed you enough to get to the big leagues in here! Nano is KILLER at helping folks understand the big math concepts in bio. MASTER THE CALC. RUB IT IN NEWTON'S FACE.
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.
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!
If an aminoacid is replaced by an incorrect one during translation, even if on the catalytic site. The cell doesnt usually cares, for it makes hundreds of proteins per hour. It is always on the DNA level where it is always looking for and correcting missmatches and various types of mutations (even having different enzymes for different mutations types). As for how does the cell does that, it really depends on what caused the mutation and what effect it had on the DNA.
The proteins that do the cell’s protein production has a double-check mechanism ensuring the code found in the dna matches up to the proper amino acid. In DNA, a set of 3 base pairs in the DNA codes for a specific amino acid or a start or a stop “codon” or encoding region.
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.
This has been explained ad nauseum. These substances have no goal, but they do have a filtered funnel to select for advantages. It's like hitting from the tee every stroke until one finally goes in vs hitting the 2nd shot from where the first shot landed, etc.
Yeah but it even gets crazier that proteins somehow fold together in a specific way and RIGHT time to function What would be the odds?? I cant even wrap my mind around that
@@shannontaylor1849 lmao where did you learn statistics? You tried to sound smart "explained ad nauseum" . Not only don't you understand the stats/maths but you don't understand the chem/bio complexity. Flipping a coins, rolling dice or shuffling a deck of cards, it doesn't have a goal and even if you got partially correct outcomes the products aren't stable so you don't get to keep the parts of the product you like and build off it. The protein problem and cellular development in general suffer from this irreducible complexity. You hit from the tee in new random direction Everytime. You role the 20 sided dice Everytime. You flip all 150 coins at once Everytime. That's just to make 1 protein and you need multiple proteins at once. The conditions on early earth were hostile, the swing, flip, or roll may be your only shot. Imagine golfing while drunk and blind folded. You can have as many swings as you want once you get out of the gold cart. You put a lot of faith in this "filtered funnel" lol
@@shannontaylor1849 1 in 1 is 100% .... You meant 1 to 1 (or 1:1) which is 50/50 lol. That's if you did one factor at a time and they only had 2 possibly outcomes, neither of which is accurate or useful in this scenario.
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.
@@IsaacMorton I agree. I suspect no one who gets taught biology has made the connection. Or maybe they have but they can’t do anything useful with it. I doubt many biologists or geneticists would have also studied computer science and computational mathematics.
Imagine all these protiens foliding into the correct parameters then attaching to their corresponding protien one sfter another while being in the exact same spot all at once. (In order to swirll first life into functionality). Where did the information come from to coordinate all the individual parts of a cell ?
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?
pretty sure the hydrophilic side is faced out and the hydrophobic side is faced inside the bilayer, making the two hydrophobic sides point at each other.
@@SlavTiger the membrane channel transport polar substances like ions and water because of it's inner hydrophilic parts. They are also inserted in the hydrophobic lipid bilayer due to it's outer hydrophobic parts. It's the opposite of the proteins inside the cell, whish has a hydrophilic outside and hydrophobic inside. My only confusion is how the membrane proteins are made.
@@Ascintony ohhhh i was confused on that bit, i wonder if the channel substances are attracted more strongly to the membrane than they are the water by some means, or if it's more mechanically fit in like an eyelet
@@SlavTiger I'm not really sure which is more attractive but the transport substances(ions and polar molecules) eventually move into the cell which is made up of water and are used for metabolic reactions
An example of this, as you mentioned with Mad Cow, are prions. Some misfolded proteins induce misfolding in other normally folded proteins because many proteins in cells homomultimerize to some extent - this refers to when multiple copies of the same protein interact with one another to form a multi-unit complex. An example of this would be the Spike on the surface of SARS-CoV-2, which is a homotrimer (3 copies of the Spike protein bound together). Proteins multimerize like this because certain amino acids on an interface of the protein are compatible with amino acids on the surface of other copies, enabling them to interact. In the case of the human prion protein (PrP), the normal fold has a series of alpha-helices formed by the amino acid series; however, when misfolded into a prion form, many of these helices become beta-strands that form a sort of solenoid structure. Both ends of this solenoid structure likely serve as points at which more proteins can be induced to misfold, ultimately leading to polymerization of proteins at these ends that form cytotoxic fibrils in neurons. Here is a short article about prion structures from Virology Blog, if you'd like to read more. virology.ws/2016/09/15/structure-of-an-infectious-prion/ As to the exact mechanistic underpinnings of how the prion induces misfolding of normally folded proteins, I'm not sure that's been uncovered in detail yet. Hope that helps.
My major was physics but I took many major level biology courses because I was interested in it. It seems to me that protein folding and all this stuff is just a model that happens to explain things satisfactorily to a human mind. We have a disease that we say is caused by misfolded proteins. We have a drug that ‘treats’ this disease, so we say that the drug is helping the proteins to fold correctly. But how do we actually know all this? We don’t (since we cannot observe it, only pseudo-observe it); it is just a model we use, but this model may not have any relation to the actual truth of what is actually going on. Beyond that, it is likely not even possible to know for sure what is going on, so a model that gives sufficient explanatory power is all that we can hope for. But there are infinite models that could work on doing this job, so why did we pick the one we are correctly using? It is because that is the path humans happened to go down, and we build off prior work, so we keep building an ever increasingly complicated edifice. It is like this in physics, too, but many don’t like to admit it. They claim we are discovering actual truths rather than just constructing a model that happens to work, a model that is just one of many. But we cannot probe those other models because it takes the effort of thousands upon thousands of humans all building off each others work. For instance, we claim the higgs bosom was ‘discovered,’ but what was actually seen? Just a small blip/deviation on a graph that has nothing to do with any actual observations of particles (because such observations are impossible). With a complicated mathematical framework and statistics, we can say the model that uses higgs bosons ‘predicated’ such a blip would occur, therefore the higgs boson exists. But there are an infinite number of mathematical models that can generate such a blip, thereby ‘predicting’ whatever we want via the injection of an explanation that is attached to the predictive model. Science claims to be empirical, but it isn’t entirely (and isn’t mostly). It is far more in the depths of rationalism, using 1% of ‘observations’ to claim stuff exists we never observed, just because our rationalism-generated model has a blip, and we observe a blip, therefore this thing we never saw, but attached to the blip via our model, exists. It is like this in molecular biology. I can observe the projectile motion of a baseball; I cannot observe anything on a molecular scale. It is all just rationalism, where 99% of stuff we believe in isn’t ever observed. But we observe something that our model attaches to the thing we cannot observe, and then we claim the thing we cannot observe has been observed (via the model) and that it therefore exists. Same with these proteins and protein folding, and drug interactions. We cannot observe how drugs actually work, so it is just a story we tell ourselves of how it works. If we could actually observe such interactions, we’d know how all drugs work, just as easily as observing someone throwing a ball, or how a mechanical watch works (actually observe it, not pseudo-observe it). But since we can’t, we don’t know how anesthesia works…. until we create a model that explains it, then we claim to know how it works (when we don’t; we just know how the model works). The model is not reality, so don’t confuse the model for reality.
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!!!😊❤
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.
there is a browser extension called DeArrow. which is a browser extension that removes clickbait by replacing it with a user sourced thumbnail and title.
@Alpha_GameDev-wq5cc I didn't label it clickbait, I nearly mistook the title for clickbait. the title doesn't give much of a hint as to the subject matter and if clearer may garner more views.
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.
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
To try everything Brilliant has to offer-free-for a full 30 days, visit brilliant.org/NanoRooms. You’ll also get 20% off an annual premium subscription.
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 them to be inserted in the lipid bilayer?
I have something can build nanobots its on my blueprint :)
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.
🤓☝️
Great correction on a disease that evolved in (west) Africa and spread to the rest of Africa and a few places in Asia through black migrations there.
@@differentone_pur the one commenting on a video about protein folding, 🤓
yup, or a charging cable that can last more than 2 months
2:36 Wish you spent more time talking about the funnel shaped energy landscape, which is the true MVP in protein folding. Cyrus Levinthal once estimated that a protein has 10^300 different conformations, and that it would take MANY times longer than the AGE OF THE UNIVERSE to fold into the native state... but this ONLY holds true if we assume a FLAT energy landscape (such as for intrinsically disordered proteins). A funnel shaped landscape ensures that regardless of the starting conformation, unfolded proteins (almost) always fold into the correct conformation in a timely manner, just like how a ball rolls down a hill. The other things you mentioned (ribosome, chaperones, ubiquitin proteasome system) are indeed important, but the energy landscape comes first
Such a sick setup for an AlphaFold video! Really excited to see what you’re building towards!
yoo clockwork! I'm only on this video because your plant series kick-started an interest in molecular biochemistry. thank you for your efforts and I'm so excited for the rest of season 2!
@@danielnoon4032 really glad my videos catalyzed you enough to get to the big leagues in here! Nano is KILLER at helping folks understand the big math concepts in bio. MASTER THE CALC. RUB IT IN NEWTON'S FACE.
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.
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!
If an aminoacid is replaced by an incorrect one during translation, even if on the catalytic site. The cell doesnt usually cares, for it makes hundreds of proteins per hour. It is always on the DNA level where it is always looking for and correcting missmatches and various types of mutations (even having different enzymes for different mutations types). As for how does the cell does that, it really depends on what caused the mutation and what effect it had on the DNA.
The proteins that do the cell’s protein production has a double-check mechanism ensuring the code found in the dna matches up to the proper amino acid. In DNA, a set of 3 base pairs in the DNA codes for a specific amino acid or a start or a stop “codon” or encoding region.
Our cells did great for eons than doctors showed up and now we have problems
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.
This has been explained ad nauseum. These substances have no goal, but they do have a filtered funnel to select for advantages. It's like hitting from the tee every stroke until one finally goes in vs hitting the 2nd shot from where the first shot landed, etc.
Yeah but it even gets crazier that proteins somehow fold together in a specific way and RIGHT time to function
What would be the odds?? I cant even wrap my mind around that
@@Akazon The odds are 1 in 1. This has already been explained.
@@shannontaylor1849 lmao where did you learn statistics? You tried to sound smart "explained ad nauseum" . Not only don't you understand the stats/maths but you don't understand the chem/bio complexity. Flipping a coins, rolling dice or shuffling a deck of cards, it doesn't have a goal and even if you got partially correct outcomes the products aren't stable so you don't get to keep the parts of the product you like and build off it. The protein problem and cellular development in general suffer from this irreducible complexity. You hit from the tee in new random direction Everytime. You role the 20 sided dice Everytime. You flip all 150 coins at once Everytime. That's just to make 1 protein and you need multiple proteins at once. The conditions on early earth were hostile, the swing, flip, or roll may be your only shot.
Imagine golfing while drunk and blind folded. You can have as many swings as you want once you get out of the gold cart.
You put a lot of faith in this "filtered funnel" lol
@@shannontaylor1849 1 in 1 is 100% .... You meant 1 to 1 (or 1:1) which is 50/50 lol. That's if you did one factor at a time and they only had 2 possibly outcomes, neither of which is accurate or useful in this scenario.
Prof. Thibault Mayor has the coolest vibe and great production in this video 🙌
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.
Holographic principle tells that information is encoded in 2d and 3d is a hologram
Makes me wonder why we aren't trying to harness it for computation
@@IsaacMorton I agree. I suspect no one who gets taught biology has made the connection. Or maybe they have but they can’t do anything useful with it. I doubt many biologists or geneticists would have also studied computer science and computational mathematics.
ive been waiting for these to come out
Thank you for making this, I really enjoyed it! 🧬
Can I ask which software did you use to render and animate the proteins?
Your visuals always amaze me
Imagine all these protiens foliding into the correct parameters then attaching to their corresponding protien one sfter another while being in the exact same spot all at once. (In order to swirll first life into functionality). Where did the information come from to coordinate all the individual parts of a cell ?
quality is LEGENDARY
Excellent presentation and synopsis - clear and no fluff. Tanks
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
Thank you DNA polymerase for keeping us alive
Sarcasm
can you make a video talking about prp and dopple?
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?
pretty sure the hydrophilic side is faced out and the hydrophobic side is faced inside the bilayer, making the two hydrophobic sides point at each other.
@@SlavTiger the membrane channel transport polar substances like ions and water because of it's inner hydrophilic parts. They are also inserted in the hydrophobic lipid bilayer due to it's outer hydrophobic parts. It's the opposite of the proteins inside the cell, whish has a hydrophilic outside and hydrophobic inside.
My only confusion is how the membrane proteins are made.
@@Ascintony ohhhh i was confused on that bit, i wonder if the channel substances are attracted more strongly to the membrane than they are the water by some means, or if it's more mechanically fit in like an eyelet
@@SlavTiger I'm not really sure which is more attractive but the transport substances(ions and polar molecules) eventually move into the cell which is made up of water and are used for metabolic reactions
@@SlavTiger are you studying a course related to biology or something
I love your channel
Lego bricks arranged themselves more or less random and somehow our consciousness pops out in it
Do we know why some misfolded proteins causing other proteins to do the same (like in mad cow disease)? At least a theory?
An example of this, as you mentioned with Mad Cow, are prions. Some misfolded proteins induce misfolding in other normally folded proteins because many proteins in cells homomultimerize to some extent - this refers to when multiple copies of the same protein interact with one another to form a multi-unit complex. An example of this would be the Spike on the surface of SARS-CoV-2, which is a homotrimer (3 copies of the Spike protein bound together). Proteins multimerize like this because certain amino acids on an interface of the protein are compatible with amino acids on the surface of other copies, enabling them to interact.
In the case of the human prion protein (PrP), the normal fold has a series of alpha-helices formed by the amino acid series; however, when misfolded into a prion form, many of these helices become beta-strands that form a sort of solenoid structure. Both ends of this solenoid structure likely serve as points at which more proteins can be induced to misfold, ultimately leading to polymerization of proteins at these ends that form cytotoxic fibrils in neurons. Here is a short article about prion structures from Virology Blog, if you'd like to read more.
virology.ws/2016/09/15/structure-of-an-infectious-prion/
As to the exact mechanistic underpinnings of how the prion induces misfolding of normally folded proteins, I'm not sure that's been uncovered in detail yet. Hope that helps.
Finely another video! 25 minutes ago nonetheless. I would love a video on how some of these misfolded proteins cause others to misfold.
My major was physics but I took many major level biology courses because I was interested in it.
It seems to me that protein folding and all this stuff is just a model that happens to explain things satisfactorily to a human mind.
We have a disease that we say is caused by misfolded proteins. We have a drug that ‘treats’ this disease, so we say that the drug is helping the proteins to fold correctly.
But how do we actually know all this? We don’t (since we cannot observe it, only pseudo-observe it); it is just a model we use, but this model may not have any relation to the actual truth of what is actually going on.
Beyond that, it is likely not even possible to know for sure what is going on, so a model that gives sufficient explanatory power is all that we can hope for.
But there are infinite models that could work on doing this job, so why did we pick the one we are correctly using?
It is because that is the path humans happened to go down, and we build off prior work, so we keep building an ever increasingly complicated edifice.
It is like this in physics, too, but many don’t like to admit it. They claim we are discovering actual truths rather than just constructing a model that happens to work, a model that is just one of many.
But we cannot probe those other models because it takes the effort of thousands upon thousands of humans all building off each others work.
For instance, we claim the higgs bosom was ‘discovered,’ but what was actually seen? Just a small blip/deviation on a graph that has nothing to do with any actual observations of particles (because such observations are impossible).
With a complicated mathematical framework and statistics, we can say the model that uses higgs bosons ‘predicated’ such a blip would occur, therefore the higgs boson exists.
But there are an infinite number of mathematical models that can generate such a blip, thereby ‘predicting’ whatever we want via the injection of an explanation that is attached to the predictive model.
Science claims to be empirical, but it isn’t entirely (and isn’t mostly). It is far more in the depths of rationalism, using 1% of ‘observations’ to claim stuff exists we never observed, just because our rationalism-generated model has a blip, and we observe a blip, therefore this thing we never saw, but attached to the blip via our model, exists.
It is like this in molecular biology. I can observe the projectile motion of a baseball; I cannot observe anything on a molecular scale.
It is all just rationalism, where 99% of stuff we believe in isn’t ever observed. But we observe something that our model attaches to the thing we cannot observe, and then we claim the thing we cannot observe has been observed (via the model) and that it therefore exists.
Same with these proteins and protein folding, and drug interactions.
We cannot observe how drugs actually work, so it is just a story we tell ourselves of how it works.
If we could actually observe such interactions, we’d know how all drugs work, just as easily as observing someone throwing a ball, or how a mechanical watch works (actually observe it, not pseudo-observe it).
But since we can’t, we don’t know how anesthesia works…. until we create a model that explains it, then we claim to know how it works (when we don’t; we just know how the model works).
The model is not reality, so don’t confuse the model for reality.
good job rediscovering philosophy of science
Great work!
oh thanks
Would be worth to mention intrinsically disordered proteins
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
Advanced Chemistry machines …. That is all we are .
What program do you use to make these animations
that's so great i cannot wait until humanity will be able to defeat disease for ever
ارتبط صوت اللواء فايز الدويري بنصر السابع من أكتوبر ربنا لا يحرمنا من صوتك
just out of curiosity , type of protein (intrinsic disoriented proteins) does not have a specific shape, is it possible to predict its structure😢
Extraordinary
2:48 laughs in intrinsically disordered proteins.
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!!!😊❤
This information makes me feel fragile. 😂
New narrator now!
Great video, thank you.
Wow! great Stuff!
Statistics! Or, as chemistry students used to joke, sadistics!
This channel is very awesome 😎
If a protein is prone to misfolding, then perhaps its primary structure is not optimal, there has to be a better one.
Let's goo!
With luck and more power of you.
nanomachines son.
top notch
2:30
😍
Atomic dimensional life designed us.
neture is the only think cleverly designed not by humans
This is so cool, and so soooo interesting, but is too much for my little mind :c
suberb!
That is some very interesting stuff.
It blows my mind that we can study something like this but cant solve some of humanities other issues. Like poverty- just amazing b
Hydrophobic VDWs eh? Sure you aren't buzzwording a bit?? ;p
Great video!
❤❤❤
Westworld
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.
there is a browser extension called DeArrow. which is a browser extension that removes clickbait by replacing it with a user sourced thumbnail and title.
What’s the clickbait? These are literally nanobots
@Alpha_GameDev-wq5cc I didn't label it clickbait, I nearly mistook the title for clickbait. the title doesn't give much of a hint as to the subject matter and if clearer may garner more views.
Bioweapon
AAAAAAAAAAAAAAAAAAAAAAAAAUG
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.
It’s called the immune system.
Protein folding is foundational to the immune system, not the other way around.
But who made our cells?
George
Science is the 20th century Gods Last Messenger.
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
This is proof of the Lord's Design.
Ok buddy
@@ILoveTinfoilHats Let me guess, it just evolves?🤣
Nuclear weapons is the proof
@@Philalethes101 Yes you illiterate
Literally the opposite… get out
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
Thanks to Darwin.
He made such evolution possible.