Obscure Biochemical Paradox May Explain Why We Can't Find Alien Life

Hi Anton, I'm a chemical biologist. There is an entire class of proteins called chaperone proteins which includes heat shock proteins (e.g. HSP60). These proteins assist unfolded proteins to fold the right way to ensure proper tertiary structure. These evolved as proteins got bigger and more complex. I work on an amyloidogenic disease which has dysfunctional chaperone activity as a component. Obviously the first spontaneously formed proteins/enzymes didn't have the luxury of chaperone proteins, but they were likely much smaller and their function much simpler.

It may be astronomically unlikely to have a protein with the same exact sequence that folds in the same way, but many amino acids within proteins (depending on the protein) can be changed without affecting the protein's function. This makes the possible number of configurations that can have near identical functionality while having different sequences rather significant.

Folding is SEQUENTIAL. Proteins are produced ONE amino acid monomer at a time, hanging from the assembly point of the ribosome. The first monomer has nothing to fold against until the second monomer is extruded. Now there are two monomers flopping around, but one of them is still stuck to the ribosome. Of all of the possible ways they can flop together, one of these ways has the maximum stability (lowest energy), so the monomers stick together in this most stable configuration and tend to STAY that way. Next, monomer THREE is extruded and comes into contact with the grouping of the previous TWO in the prior maximally stable configuration. So the new monomer is bumped into by the TWO previous monomers, already folded together, which bounce around and form the maximally stable configuration CONSISTENT with the previous folding. There are NO FREE CHOICES, because, at each stage, only one configuration is maximally stable GIVEN the configuration in which the prior monomers have folded. Hence, at each stage, there is only ONE configuration possible. Hence, THERMODYNAMICS drives the folding process. It does not matter if other configurations are possible, even if some of them are more stable than the current configuration, because the previous configuration is already locked into place. I am ignoring the complexities introduced by chaperone proteins, which are already out there.

The solution to this paradox is that during the folding process, proteins pass through a series of INTERMEDIATE states that reduce the number of POSSIBLE conformations. These intermediates are like ANCHOR points that help direct the protein to its "CORRECT" structure. In addition, hydrophobic interactions also play an important role in the folding process.

This is a rare case where I disagree with you, Anton. For a start, the problem is predicting the shape given the sequence of proteins, not the unordered bag of them. (That still made it one of the hardest scientific problems we know.) But the proteins don't then fold randomly, physical forces (like electrostatic attraction) act all along the chain, causing folds to start at various points. As they fold, new parts of the chain come close enough to affect one another to start fresh folds of the already-folded sections. So there's a logarithmic process at work, as well. Because AlphaFold 2 predicts the structures with nearly the same accuracy as experimental determination, and because proteins do tend to fold predictably in nature, it means the process cannot be a random one, it must be following physical laws that aren't overly sensitive to initial conditions. So in that sense it's similar to predicting the path of a ball rolling down a surface under the force of gravity (just with the parameters of the problem scaled up hugely).

Anton, the aliens appreciate your continued efforts to conceal their existence.

So we made a machine to understand a process, and now we need to understand how the machine understands that process

Appreciate you Anton. Your videos are always a delight. Sometimes it's just nice to hear the "hello wonderful person" and be reminded it's our ability to learn and wonder at the mysteries that often makes us so wonderful.

I remember when I was still a Biochem student my professor strictly warned me to not try working on optimizing rubisco or any rubisco research. He said that there have been many who have wasted their whole careers in doing so, and that if evolution could have optimized rubisco it would've found a way to do it by now.

Damn Anton, mad respect. I had no idea you were going for your PHD. You are very humble

Thank you Anton. You are very good at simplifying the complicated, and I love that you share a bit about yourself along the way. 🙂

Not sure levinthals paradox can be applied to alien life. Also it really isn’t a paradox anymore. Just because we don’t understand the folding mechanism doesn’t make it a paradox…

Hey dude, really sorry to hear about your mom. Losing a parent is always really hard. Though I am happy for you that you were able to use that tragedy to reevaluate what you wanted out of life and chose to pursue what makes YOU happy. Proud of you buddy

If I remember correctly one of the leading hypotheses out there for how proteins fold so quickly is the energy landscape funnel model where the protein initially samples a wide range of conformations but as soon as it becomes slightly more folded the conformations it can sample become drastically limited, kind of like cutting off entire branches of a decision tree. This is in line with our understanding of thermodynamics with a highly flexible state being an unstable one for most proteins (now intrinsically disordered proteins are a whole other story) and the experimental evidence of protein (un)folding in domains and through specific stages. The funnel hypothesis also explains why some proteins are prone to aggregation and how refolding a protein is possible but needs an external boost like a chaperone protein. Great video though, love your content!

Some good observations on this so difficult problem. Understanding life (and, worse still, its origin) is a unique scientific problem where intuition from other fields often fails because it is the very rare, very exceptional behaviour which ends up being most important, through the magic of natural selection.

Anton's foray into the biological sciences is still nascent but i admire his enthusiasm and we can all keep that in mind and offer positive and wonderful information 🤗

You just made the channel even more valuable. I love it when multi-disciplinary science comes together!

Anton so many of us are all glad you didn't become a doctor. Me personally you have taught so many things that have lead into learning so many other things in several fields. I have been able to make connections in society and my surroundings that I never would have if I hadn't watched some of you and other Youtube Teachers videos. Seriously man Appreciate you!

Love your channel Anton. I never realized that you lost your mom eventually decided not to become a doctor but do remember you had background in biochemistry. I had sort of the reverse situation in a way. My dad died of ALS when I was younger, so I had decided to become a doctor, but eventually I realized this was not a pure motivation of mine, but was fueled by revenge and my inability to accept death. Eventually I decided to become a math major when I entered college, and rediscovered that childlike wonder in it, unclouded by grief.

@Anton, we all benefit so much from your analysis and insights, and I personally am very grateful for your regular videos. Thank you.