Possible Cause of Misfold

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Possible Cause of Misfold

Postby stevedking » Sat Dec 22, 2012 5:39 am

I going to throw onto the table here... an idea that may cause misfolds. It's just a thought.

What if the physical geometry of the hydrophobic amino acid sections ... with respect to the entire protein ... are the key to how the protein folds? Let me explain. Specifically ... side chain hydrophobes.

1. Let's assume that a given perfect protein (P1) has a length (PL), and in an aqueous solution it has a mechanical resonant frequency (PFR). Physically, the protein is twisting and bending at some resonant frequency.

2. Now assume for the moment that this protein (P1) folds perfectly ... because ... the geometry of every amino acid is perfect.

3. To create a misfold, let's take this same protein (P1) and let's modify the geometry of one hydrophobic side chain section and call it protein (P2). Since the side chain is nonpolar, it moves in the aqueous solution causing a moment about its side chain arm, which in turn torques the entire protein. Basically, the hydrophic sections act as an energy delivery mechanism to the protein string.

CASE A: If the arm is too long, it will torque the protein at a frequency lower than (PFR) ... which in turn will cause the protien to misfold.
CASE B: If the arm is too short, it will torque the protein at a frequency higher than (PFR) ... which in turn will cause the protien to misfold.

Any thoughts?
:|
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Re: Possible Cause of Misfold

Postby bruce » Sat Dec 22, 2012 6:48 am

It sounds pretty logical to me, though I do have a few questions.
1) Why was it necessary to replace P1 with P2? If there was a geometric change, what caused it? Or, perhaps the underlying geometry was identical and the only difference between P1 and P2 was a different distribution of energy (due to thermal randomness) allowing the transition to a less likely state.
2) I think assuming a single PFR is overly simplistic. With many thousands of degrees of freedom, there would be many resonant frequencies of different groups of atoms. Any one of those groups might be perturbed sufficiently to create a misfold. It seems that the chances of the protein folding correctly would be pretty poor without the classical concept of the protein seeking a minimum energy shape, leaving us to assume there are multiple local energy minimums, with very, very few of them having a significantly long "half-life" (or whatever protein scientists call the dwell time in the semi-stable states).
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Re: Possible Cause of Misfold

Postby stevedking » Sat Dec 22, 2012 10:38 pm

Let me restate my case in a different way. Let's look at the amino acid "Leucine". If one of the CARBON atoms is an Isotope with a mass different from Carbon 12, then the side chain will have a mass that is different from Carbon 12. Under nanoscales, say Carbon 13, would be a very large change in mass and would affect the entire twisting and bending motion of the protein. ... changing the PFR. An Isotope changes the geometry of the molecule in which it resides... ever so slightly, but it does.

CASE 1: If the Carbon atom is Carbon 12, then the entire protein will have the normal_PFR, and fold correctly. (lets assume that normal_PFR is the PFR needed to go to lowest energy state). Assume all other atoms are of normal mass.

CASE 2: If the Carbon atom is an Isotope with a mass greater than 12, then the entire protein will have a PFR < normal_PRF, causing the protein to misfold. The protein would have giant twisting and bending trajectories... possibly yanking it out of a minimal energy state.

CASE 3: If the Carbon atom is an Isotope with a mass less than 12, then the entire protein will have a PFR > normal_PRF, causing the protein to misfold. The protein would have small trajectories in twisting and bending.... possibly never reaching a minimal energy state.

In summation, if the protein is twisting and bending out of range from normal_PFR, then this change in mass from the Carbon Isotope may cause the protein to prevent itself from "LOCKING" into place BECAUSE the mechanical energy is yanking it out of its normal locked and correctly folded geometry.... or it may never reach a Locking state.

Note: I am being very very simplistic about the resonant freq PFR because it would be impossible to describe the various resonant freq in a string. I cannot discuss Fourier Series analysis in a short forum like this. So... lets keep it simple for the sake of sanity.
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Re: Possible Cause of Misfold

Postby Jesse_V » Sat Dec 22, 2012 10:51 pm

Complicated stuff, but it does seems like a valid argument and it makes sense to me that these two cases could result in misfolded proteins. I just never considered resonance before!

In essence, a simple transcription error creates a point mutation which in turn results in one of these two possible cases, which could each could cause misfolding. Interesting.
Pen tester at Cigital/Synopsys
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Re: Possible Cause of Misfold

Postby stevedking » Tue Dec 25, 2012 4:48 am

My posts my seem deficient in worldly wisdom, though I'm not a biochemist, I make posts from a brainstorming perspective -- in hopes that the posts will inspire a new line of thought.
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Re: Possible Cause of Misfold

Postby codysluder » Tue Dec 25, 2012 8:01 pm

So the question changes from which minor aberrations [point - mutations) are self-correcting and which cause the protein to get permanently stuck in an unexpected shape.
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Re: Possible Cause of Misfold

Postby Jesse_V » Tue Dec 25, 2012 8:34 pm

codysluder wrote:So the question changes from which minor aberrations [point - mutations) are self-correcting and which cause the protein to get permanently stuck in an unexpected shape.

Back in 2006, F@h was used to study point mutations, their relationship to the stability of a given protein, and the implications towards cancer: http://www.sciencedirect.com/science/ar ... 3605016736
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