danby

danby t1_jbz36wk wrote

> The intermediate states are irrelevant

Irrelevant to what? They seem pretty relevant if we're studying protein dynamics.

> It is only the free-energy difference of the two states (bound and unbound) that matter.

It's the only information that matters to what? If we're studying protein dynamics can you predict if a protein undergoes a change in structure form the change in free energy alone?

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danby t1_jbz2kzo wrote

Why on earth would we be only interested in simple cases?

MD is fine in many cases (very, very good in some) but it is absolutely not sufficient to fully model and understand the dynamics of proteins. We know the forcefields we have are lossy and not great for many applications when it comes to proteins. Simulations of long time spans or large protein rearrangements are generally very poor.

> You could say we are limited with what kind of computing power we can apply in complex systems.

Well yeah we limited there.

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danby t1_jbtmzen wrote

I don't think we'd regard proteins as rigid bodies. Lots of what makes working with protein structure hard is that we don't have a good way of modelling the dynamics of proteins. The hydrogen bonding network is quite flexible.

Ligand induced structural change is indeed an important type of ligand binding but there are many examples of binding without structural shifts.

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danby t1_jbopbwg wrote

Minimal genome experiments generate organisms that aren't free living so they aren't really aimed at generating something like the LUCA. Mostly these experiments are trying to discover the minimal set of house keeping genes that can maintain a living cell, there's no reason to believe the LUCA was like that, nor any reason to believe that the LUCA had a minimally sized genome.

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danby t1_jbol01z wrote

Probably not. The last universal common ancestor (LUCA) of all life, circa 3.6 billion years ago, was bacteria-like and most likely to be free living (or somewhat colony forming). It's unlikely that a free living organism could have a genome as small as 438 genes. We also know that most major protein structural families data back to that period so a fairly complete repertoire of possible biochemical functions would have been within evolutionary reach to the LUCA. So it seems likely the LUCA was quite sophisticated from a biochemical function POV. We see that contemporary bacterial genomes tend to favour minimum levels of redundancy but that isn't the same as having smaller numbers of genes. Different types of bacterial genomes have very diverse counts of the number of genes present. Between these observations there's little reason to suspect that the LUCA's genome was minimal.

Anything older than the LUCA, such as pro-genotes (things before "modern" genomes appeared) or even earlier forms would have been substantially different to an organism with an organised genome of 438 genes. The further back in time you go towards the abiotic origin of life the more "weird" and less cellular early life probably was. There remains a reasonable chance that the earliest self replicating systems were just soups of nucleotide chains, which would arguably be the earliest life-like things on earth (circa 4.6 bya), and that's quite unlike a genome-containing cellular organism.

It remains a very open question what the earliest self-replicators that gave rise to cells might have been but all the options are pretty weird. Here's a somewhat decent summary of some models

https://www.bionity.com/en/encyclopedia/Origin_of_life.html

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danby t1_j9jy3dw wrote

A problem here is how we teach evolution; that traits (and by extension) genes are selected. But the reality is in any given environment only a subset of traits are under active selection pressure. Most genes are free to drift by chance and appear and disappear.

I have somewhere of the order of 20-24k genes. I live in an environment where we estimate that 2000-4000 humans gene show adaptations to settled agriculture and cities. Less than half of human genes are estimated to be house keeping (i.e. required by all cells)

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danby t1_iz4f0u9 wrote

It's moderately well observed that animals appear to engage in behaviours that are self-medicating

https://en.wikipedia.org/wiki/Zoopharmacognosy

Almost all Gibbon skeletons that are found in the wild have signs of healed fractures and breaks. Which indicates while injured they must be cared for (such as having food brought to them) while the bones heal, though that isn't evidence that they understand they are providing medical care so much as bringing food to their partner who can't/won't

https://en.wikipedia.org/wiki/Gibbon

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danby t1_iwpk812 wrote

> The ETC pumps electrons across the inner mitochondrial membrane from the matrix to the intermembrane space to create the proton gradient.

This absolutely does not happen.

Electrons are transported from complex to complex arranged as a chain hence why it is called the ElectronTransport Chain. And indeed this is how it is illustrated in both the 1st two diagrams of your link, where the "path" of the electron(s) is between complexes within the membrane and not in to the intermembrane space. You'll note in the 2nd diagram that at the end the "free" electrons are passed from complex IV to Oxygen in the matrix because oxygen is the final acceptor of electrons in the ETC. This is where the electrons end up, not in the intermembrane space. Free electrons are not accumulated in the intermembrane space (I'm not even sure physics allows free electrons to accumulate outside of some exceptionally rarefied circumstances)

The oxidisation of free FADH and NADH provides high energy electrons at the start of the chain, as the electrons transition between complexes they lose energy and this free energy is "used" to move the H+ ions in "solution" within the matrix to the intermembrane space. That is, the ETC complexes pump protons across the inner mitochondrial member to the intermembrane space. This establishes a concentration gradient as H+ ions are highly concentrated in the intermembrane space.

Also the whole system wouldn't work if the intermembrane space was filled with free electrons while complexes I - IV were "pumping" H+ ions there. If that were the case the H+ ions would immediately neutralise and become hydrogen atoms. ATP Synthase works because it can make use of the concentration gradient between "free" H+ ions in the intermembrane space and the lack of "free" H+ ion in the mitochondrial matrix.

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danby t1_iux8h0s wrote

After a quick google the answer is none of these. This is a rare condition where you have an allergy to cat or pork epithelium (typically it would be some protein in the skin or mucus membranes of the animal). And being exposed to the other causes a severe over reaction.

But if your pork allergy isn't to an epithelial protein then you wouldn't be at risk of being exposed to cat epithelia tissue

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412402/

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danby t1_iuw8lt1 wrote

> the reaction would be much more severe even fatal when coming in contact.

Why? As the paper shows, in Table 2, patient Fel D 1 specific IgE and IgG4 bind significantly less strongly (often by an order of magnitutde less) to the big cat proteins. I'll admit it's been a fair while since I studied much immunology but my understanding is less binding of Igs is associated with less immune system activation and less strong immunological responses.

(though of course a person could later go on to develop a specific allergy to a big cat fel d1 homologue)

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danby t1_iuvnkgj wrote

There are 3 proteins that humans are allergic to in domestic cats. The main one is Fel d1, a protein secreted from the sebaceous glands and present on the skin and fur. It is also present in small amounts in cat saliva. The other two allergens are the proteins Fel d4 and Fel d7 these are both salivary proteins. Mostly you're exposed to these two via the cat's fur as they are deposited there during grooming, though being licked by a cat will also do it. Individual cats also express differing amounts of each of these proteins. So, if you are Fel d4 sensitive but a specific cat doesn't express any (or minimal amounts of) Fel d4 you'll not be allergic to that specific cat. Though you can be allergic to one, two or all three of the cat allergens.

Whether you would be allergic to big cats comes down to two things, do big cats also produce homologous proteins to the three domestic cat's proteins? And are the big cat versions of these proteins sufficiently similar to still invoke the immune response?

Well, it turns out that people have already tested some of this for Fel d1. And the answer is that if you are allergic to house cats your antibodies will bind to the big cat version of Fel d1 but that your antibodies don't bind as specifically/strongly to the big cats' versions of the protein. This gives us answers to our two questions; Yes, big cats produce a Fel d1 homologous protein that your anitbodies can bind. But, as the binding isn't as strong there's a good chance any allergic reaction will be weaker than your reaction to house cats.

https://pubmed.ncbi.nlm.nih.gov/1695231/

There seems to be a lot less information about Fel d4 and Fel d7. But I'd assume as all cats are pretty closely related the big cats likely have their own homologous versions of these proteins as well and somewhat similar results are also likely

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danby t1_iusfjb0 wrote

There's still a lot of arguments over what kind of musculature and what types of feathers and how sparse they might have been so that actual appearance is still open to a lot of artistic interpretation, but there's increasing evidence that many dinosaurs would have been feathered. And we have fossil evidence of this for about 50 species (I think)

And for T.Rex we know that some close relatives had feathers: https://institutions.newscientist.com/article/mg25133560-800-t-rex-with-feathers-chinas-fossils-are-rewriting-the-dinosaur-story/

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danby t1_iurb7az wrote

> Assuming the most conserved are the oldest, candidates for 'oldest sequence' are the RNA sequences for the 16S and 23S ribosomal subcomponents, plus assorted tRNA sequences (all involved in converting RNA into protein),

Interestingly the emergence of a unified means of RNA translation is likely what drove the emergence of genome based organisms (rather than the prior progenotes) and in turn gave rise to the Last Universal Common Ancestor of all life (circa 3.6-3.9 bya). Which is why tRNA and ribosome sequences are among the most ancient sequences we have.

Here's a very nice paper summarising what we know about this molecular evolution and

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008548/

And my favourite Carl Woese paper on the subject

https://pubmed.ncbi.nlm.nih.gov/9618502/

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danby t1_islfy04 wrote

> To me that is why 0.6% variance within humans is a lot

Sure but this includes non coding and repetitive DNA which between individuals is somewhat unconstrained. If you look at only protein coding genes you get back down to variances closer to 0.1%

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danby t1_isis6zk wrote

> So if a gene/allele gets moved to a different place, it still counts as no difference.

Definitely not. Translocation often leads to or implies different expression of genes. As an aside many, many translocations over large amounts of evolutionary time can lead to things like chromosome loss and/or speciation events. These are important forms of genetic change/mutation that do lead to important functional change. And they do make genomes quite different in ways that aren't measurable by simple percentages.

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danby t1_ishjkfs wrote

Agreed. "Proportion of non-shared base pairs" is at least a decent enough, semi-objective way to compare the differences between two genomes without getting too far in to the weeds about what exactly constitutes a difference. There are, in the end of the day, lots of differences that simply can't be expressed as a percentage difference (like gene/chromosome translocation)

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danby t1_iqtgbe9 wrote

> It's probability. There are thousands, millions, maybe infinite different tangled states a cord can be in, and exactly one non tangled state

This can not possibly be true. Or rather I feel you're conflating topology (does or doesn't contain a knot) with physical pose (the real physical position of a string).

Consider protein folding. No protein forms true knots when they fold but we know there are [nearly] infinitely large number of states any non-trivial protein chain can adopt. And so it must be with regards pieces of string; there are surely an infinite number of unknotted poses a string can adopt and an infinite number of poses which also contain knots.

So yes there is only one topology that has no knots (by definition of the problem) but a string with that topology can still explore nearly infinite numbers of physical states. And this is somewhat reflected in the paper you've linked. In their tumbling experiment their string only knots about 33% of the time. Because there is a very, very large set of unknotted physical states that can be explored.

In the paper they also describe the sequence of braiding steps that generates knots, As this is an ordered set of moves this surely indicates the knotting can't be a purely entropy driven process. Certainly whatever energy surface the string is moving over can't be purely smooth and downhill. Which is likely also why in their tumbling experiment only a third of the tests results in knots, as there is some manner of "energy" barrier that must be surmounted to get to a knotted state.

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