Folding questions

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Folding questions

Postby Ricorocks » Sun Feb 19, 2017 6:46 pm

From first amino acid (becoming part of a new protein) to final folded state. Does folding speed (how quickly folds happen) start slow (amino acid #1) then build speed to, Folding max spd. Then slows/stops as final stable shape is reached?

How does the protein get past the cell wall, is that a endoplasmic reticlum?

Have many/few patterns been identified, in folding?
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Re: Folding questions

Postby bruce » Mon Feb 20, 2017 7:10 pm

There are some pretty good FAQ at the Stanford website ... and I like https://en.wikipedia.org/wiki/Folding@home, too.

The folding process depends on the forces of attraction/repulsion between atoms and probably would follow Newton's Laws at absolute zero, but proteins don't spend much of their life at absolute zero. At "reasonable" temperatures, atoms move somewhat randomly. (See https://en.wikipedia.org/wiki/Brownian_motion). FAH takes both of those effects into account so that the mathematical results resemble the physical results.

There is a constant exchange between potential energy and kinetic energy as the protein seeks to settle from a high energy state to a minimum energy state. There are lots of bumps and hollows along that road and a protein spends a lot of time sort of stuck in an energy hole until the random energies all happen to add up to enough to get it over one of the surrounding hills, at which point it moves rapidly to the next energy hole. (Look carefully at the Markov state model image on the Wikipedia article and imagine you're looking down on a rough surface with those bumps and hollows are pointing up at you.) There are many paths from the unfolded state to the folded state, and along each path, the protein will spend some time in the colored states before following an arrow toward the folded state.

Along each path, most of the time is spend stuck ... i.e.- not folding -- before being kicked out of that hole. Asking about the overall folding speed has very little meaning.

Generally, FAH starts anumber of Run,Clone locations on that bumpy surface and maps out the popular hangouts denoted by the colored shapes. Once there's a sense of where the protein dwells, a new project can be started from each of those energy holes to study all of the possible surrounding arrows, finding new ones, and mapping how strong each path is. i.e.- The randomness of the process is better studied if one can filter out the important jumps between local energy minimums from the unimportant ones.
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Re: Folding questions

Postby Ricorocks » Mon Feb 20, 2017 8:19 pm

I was thinking the 'bonding' atoms satisfying electron outer shell, by bonding to another amino acid, was the force & as more amino acid joined, the more torque/folds occurred more rapidly, till the finished product or stable protein state.

Looking around I see, for exiting cell wall by a protein. Can be (depending on source) golgi or vesicles, not sure.

DNA is read in triplets (using combos of G, C, A, T) So it seems reasonable, that protein patterns emerge.

Is P53 also called chaperone? Depending on few or many, one can get Cancer or AHD, not common for both diseases. Many chaperones less likely cancer more AHD, Fewer Chaperones more likely cancer than AHD

Reading to do now
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Re: Folding questions

Postby Ricorocks » Wed Feb 22, 2017 2:55 am

@Bruce - " Asking about the overall folding speed has very little meaning." Agree! Also agree with 'potential & kinetic' energy comments from your post.

For overall understanding (no scientific aha here), seems logical amino acid #1 would be a potential energy > then amino acid #2 bonding to #1 would be kinetic energy, which would gain momentum with additional amino acid 'bonding' to a peak point, then the process would slow, till stable/functional/potential energy state is reached. So if folding speed goes from, zero to peak to zero energy. I'm curious as to any patterns if mis-folding occurs early or late state folding. And if DNA can predict, early or late stage folding mistakes, or vice a versa.

FYI - Bruce I remembered the brownian movement thing. Totally lost as in Rorschach images for markov. Got two good eyes but still don't see. GTGEBSDS syndrome
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Re: Folding questions

Postby bruce » Wed Feb 22, 2017 6:36 am

The total folding progress from fully denatured to fully folded state consists of a number relatively long zero speed intervals punctuated by several a very rapid movement from one almost stable state to another almost stable state with lower energy. The "almost stable states" are local energy minima surrounded by a crater of higher energy. The colored spots on the markov picture shows the shape of the protein when it's in those almost stable states. The magnitude of the arrows denote the probability of transitions from one such state to another.

In fact, when the protein is stuck in the crater surrounding a local minimum, it's still experiencing Brownian movements but the overall motion isn't enough to kick it out of that local minimum. Eventually it penetrates one of the crater's walls and jumps to another local minimum.

Back when I ran seti@home, they made a point that they have to analyze a lot of WUs where nothing interesting is found just so they can select the rare ones that might have something interesting. In a sense, FAH could say the same thing: The actual transitions are interesting, but there are lots of uninteresting periods of time between them.

You'll notice from the Markov picture, that there are a number of different paths by which the protein might go from denatured to folded. In that picture, there's only one fully folded state and all paths lead there but it wouldn't be hard to imagine that there's a branch to an alternate final state that has a deep enough energy crater to make it stable at body temperature (a misfolded state).
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