Fundamental as Fewer Bits by Terry Bollinger

Giovanni,

Well... hmm, it's Feb 27 but this is still working, at least for a while.

Thank you for your very kind remarks! I'll be sure to read your essay, as I try to do whenever anyone posts, even though the rating periods is over.

(Or can we still post, just not rate? Sigh. I must read the rules again...)

Cheers,

Terry

Peter,

Thank you for the follow-up, but at 12:30 AM I'm not quite sure I followed all of that? I assume you did see my long posting at your site? I'll try to read your posting above again when I'm awake... :/ zzz

Cheers,

Terry

Ulla,

Thank you for your generous and kind remarks! It's past the rating period now, but I'll be sure to take a look at your essay tomorrow (today?)

Cheers,

Terry

Giovanni,

I have finally figured out how to finds posts like yours! I simply search by date, e.g. "Feb. 27" for this one. It has been very hard for my poor brain to find entries when they show up in the middle of the blogs, both in mine and in others.

Thank you for your positive and constructive comments! Also, thanks for that bit of info on how just the ratings close, not the commenting. I for one will be more likely to show up, not less. The ratings part is designed like a Hunger Games incentive program, so having it gone makes me feel like a more unfettered form synergistic interactions is now possible.

I am particularly appreciative of your quick list of essays worth examining. I plan to look at them, hopefully all of them! I keep finding unexpectedly interesting points in so many of these essays.

Finally, please feel very free to post in my essay thread anytime you want to. It never even occurred to me that it might not be the right "spot" for you to do so. (Come to think of it, considering some of the humongous posts that I've put on other folks' threads, I guess it's sort of a given that I'm not too worried about people cross-posting, isn't it?)

Cheers,

Terry

Gordon,

Good comments, wow. I've had some difficulty (external factors) getting back to my queue, and this is not a complete reply. But two quick items:

-- When I say "QM is the physics of that for which history has not yet been written," probably the best way to explain it is Feynman's integral-of-all-possible-histories QED concept. What that concept says is remarkably simple: If you track every possible way that an event could happen from its start to all points in the future that could be touched by that event, then add them all together using particle phase along those paths, you end up (voila!) with, well, the quantum wave function for the event. The paths whose phases match up reinforce each other, and give the highest probability outcomes.

That is, every wave function can also be interpreted as a "bundle" of possible histories, but only if the wave function has not yet been "collapsed". And by "collapse", I really mean only this: Until you poke the wave function hard enough to force it to say which of those many possible histories in the wave function has to produce an actual event or particle. Extracting such information, such as by letting an electron wave function hit a photodetector, creates history. There really is no meaningful distinction between the two: information is history.

In most presentations the "history" or path implications of collapsing a wave function is not emphasized, in part because I think people are uncomfortable with the idea that some parts of the past have not yet been set. But if you detect a photon whose wave function is a hundred light years in diameter (happens all the time!), you are inevitably also setting a "history" for that photon that causes it to land on earth and not on some distant star. For pilot wave folks this is flat-out trivial: The "real" particle was always headed to earth! For folks like me who respect but cannot accept the pilot wave model, it gets... complicated, and requires a rather ragged-edge concept of when the past finally gets set.

-- Bell: Argh, I don't recall the reference, but I can assure you with something like 99% confidence that Bell was trying to disprove entanglement. He was a pilot wave person and proud of it, saying it helped him come up with his theorem (that part at least I think is from Speakable and Unspeakable).

The reason he comes over as the opposite is, I'm pretty sure, a case where he was leaned over very hard to not seem biased. He truly did not want to be one of those people who adamantly finds what they want to find; he wanted the data to speak for itself.

Enough, it's late...

Cheers,

Terry

Biomolecular Renormalization: A New Approach to Protein Chemistry

Terry Bollinger, 2018-03-05

Abstract. In every cell in your body, hundreds of proteins with very diverse purposes float in the same cytosol fluid, and yet somehow rapidly and efficiently carry out their equally diverse tasks including synthesis, analysis, demolition, replication, and movement. Based on an earlier 2017 FQXi Essay contest mini-essay on the importance of renormalization and the Nature paper below, I propose here that the many protein chemistry pathways that go on simultaneously in eukaryotic and prokaryotic cells are enabled, made efficient, and kept isolated by a multi-scale biomolecular renormalization process that breaks each interaction into scale-dependent steps. I conclude by discussing ways in which this concept could be applied both to understanding and creating new biomolecules.

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NOTE: A mini-essay is my attempt to capture an idea, approach, or prototype theory inspired by interactions with other FQXi Essay contestants. This mini-essay was inspired by:

1. What does it take to be physically fundamental by Conrad Dale Johnson

2. What if even the Theory of Everything isn't fundamental by Paul Bastiaansen

3. The Laws of Physics by Kevin H Knuth

4. The Crowther Criteria for Fundamental Theories of Physics

5. The Illusion of Mathematical Formality by Terry Bollinger (mini-essay)

Non-FQXi References

6. Extreme disorder in an ultrahigh-affinity protein complex, March 2018, Nature 555(7694):61-66. Article in ResearchGate project Novel interaction mechanisms of IDPs

7. Extreme disorder in an ultrahigh-affinity protein complex, March 2018, Nature 555(7694):61-66. NOTE: This article is behind a (large) paywall.

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Background: Scale-Dependent Protein Interactions

In the March 2018 Nature paper Extreme disorder in an ultrahigh-affinity protein complex, the authors provide a fascinating and extremely detailed description of how certain classes of "intrinsically disordered proteins" (IDPs) can bind together based initially on large-scale charge interactions that are then followed by complex and remarkably disorderly bindings at smaller size scales. The purpose of this essay is not to analyze this specific paper in detail -- this excellent paper does that very well for its intended biochemistry audience -- but to show how an external set of physics-derived, scale-dependent renormalization framework can be used not only to provide an alternative way to look at the interactions of these proteins, but to understand a broad range of large-molecule interacts in a new and potentially more unified and analytical fashion. This broader framework could in principle lead to new approaches to both understanding and designing proteins and enzymes for specific objectives, such as how to bind to a wide range of flu viruses.

The Importance of Approximation-At-A-Distance

The initial approach of two IDP proteins via simple, large-scale difference of electrical charge appears to be an example of biological multi-scale physics-style "renormalization." By that I mean that the proteins are interacting in a hierarchical fashion in which large, protein level charge attractions initiate the process while the proteins are still at some distance from each other and details are irrelevant due to charge blurring. This is the central concept of renormalization in, say, the QED theory of electron charge: You can at large distances (scales) approximate the electron charge as a simple point, much as you are approximating the complex protein charge as a "lump charge" in first stage.

As the proteins approach, more detailed patterns grow close enough to become visible, and the initial lump-protein-charge model fails. One must at this point "renormalize," that is, drop down to a smaller, more detail scale that allows analysis in terms of smaller patterns within smaller regions of the protein. In the case of the dynamic and exceptionally disorganized IDP proteins, these later stages result in surprisingly strong bindings between the proteins. More will be discussed later about this intriguing feature, which I believe can be reinterpreted as a more complicated process that only appears to be random and disorganized from an outside perspective. It is at least possible, based on a renormalization analysis, that this "randomness" is actually a high-density, multi-level transfer of data. This transfer would be enabled by the large number of mobile components of the protein behaving more cogs and wheels in a complicated machine than as truly random parts. Alternatively, however, if binding truly is the top priority for the proteins, the moving parts could also accomplish that without using the resulting bindings as data.

Broadening the Model: Multi-Level Attraction and Rejection

However, even more interesting than detailed binding when proteins grow closer is the possibility that the interactions at that level reject rather than encourage further interactions. Such cases might also be very common, possibly even dominant. You would have a "dating service" that allows the proteins to spend a small amount of time and mobility resource to check out a potential match, but then quickly (and this is important) realize at low cost the match will not work. Amplify such low-cost rejections by huge numbers of protein types and individual instances, and the result is a very substantial overall increase in cellular efficiency.

If however the next level of charge-pattern detail does encourage closer attraction, the result would be to head down the path of repeated downward renormalization of scale, as individual sheets and strands move close enough to "see" more detail. If the proteins were exact matches to begin with, then renormalization (which in this contex just means "scaling down to see greater levels of charge pattern detail") would proceed all the way down to the atomic charge level. The "dating service" would be a success, and the match accomplished. But more importantly, it would be accomplished with high efficiency by avoiding getting into too much detail too quickly.

Broader Implications of Multi-Scale Protein Interactions

There are a number of very interesting potentials in such a renormalization interpretation of protein-to-protein binding. Importantly, most of these potentials apply to pretty much any form of large-bio-molecule binding, including emphatically DNA) and (to me even more interesting) enzymatic creation of novel molecules. These potentials include:

o Efficient, low-time-cost, multi-stage elimination of non-matches.

Proteins (or DNA) would be able to approach at the first scale level based on gross charge, then quickly realize there is no match, and so head off to find the right "machinery" for their tasks. The efficiency issue is huge: Repeated false matches at high levels of detail would be very costly, causing the entire cell to become very inefficient.

o Increased probability of correct protein surface matchups.

Or, conversely: Lower probabilities of protein matchup errors. A huge but somewhat subtle advantage of multi-scale attraction is that it gives each new level of smaller detail a chance to "reorient" its components to find a better local match. One way to think of this advantage is that the earlier larger-scale attractions are much like trip directions that tell you which interstate highway to take. You don't need detail at that level, since there will in general be only one interstate (one "large group area match") that gets you to the general region you need for a more detailed matchup. Only after you "take that interstate" and approach more closely do the detailed "maps" show up and become relevant.

o Complex "switch setting" during the multi-scale matchup process.

Since proteins are not just static structures but nano-scale machines that can have complex levels of local group mobility (more later on the implications of that), such lower-scale matchups can be more than just details showing up at the finer scales. They can also re-orient groups and structures, which in turn can potentially "activate" or "change the mode" of one or both proteins, much like turning a switch once you get close enough to do so. These "switches" would of course themselves be multi-scale, ranging e.g. from early large-scale reorientations of entire beta sheets down to later fine-scale rotations of side groups of individual amino acids. What is particularly interesting about this idea is that you potentially could program remarkably complex sequences in time and space of how such switches would be reset. There is potential in multi-scale, multi-time switch setting for a remarkable degree of relevant information to be passed between proteins.

o Multi-scale adjustment of both specificity and "stickiness".

As with gecko feet, if the goal of the protein is aggressive "grabbing" of a range of some broad class of proteins, this can be programmed in fairly easily via the multi-scale model. It works like this: If the purpose of the protein is to bind and entire class of targets based on overall large-scale charge structure (and please note the relevance of this idea to e.g. ongoing efforts for universal flu vaccines), then the next lower level of scale in the protein should be characterized by extreme mobility of the groups that provide matching, so that they can quickly rotate and translate into positions that allow them to match essentially any pattern in the target molecule.

Conversely, if certain patterns at lower scales indicate that the target is wrong, then those parts of the program should present a rigid, immobile charge pattern upon closer approach. Mobility of groups thus becomes a major determinant of both of how specific the protein is, and how tightly it will bind to the target.

o Energetic activation of low-probability chemical reactions.

This is more the enzyme interpretation, but it's relevant because multi-scale provides a good way to "lock in" just the right sequence of group repositions to create highly unlikely binding scenarios. Imagine first large groups then increasingly smaller and more specific groups all converging in attraction down to a point where some small group of atoms is forced into an uncomfortable positioning that normally would never occur. (This is a version of the multi-level-switch scenario, actually.)

At that point a good deal of energy is available due the higher-level matchups that have already occurred; the target atoms are under literal pressure to approach in ways that are not statistically likely. And so you get a reaction that is part of the creation of some very unlikely molecule. This is really quite remarkable given the simplicity and generally low-overall-energy level of amino acid based sequences, yet it comes about fairly easily via the multi-level model.

Another analogy can be used here: Imagine trying to corral wild horses who have a very low probability of walking into your corral spontaneously. Multi-scale protein matchup energetics then are like starting with large-scale events, say helicopters with loudspeakers, as the first and largest-scale way of driving the horses into a certain region. After the horses get within a certain smaller regions, the encirclement process is then scaled down (renormalized) to use smaller ground vehicles. The process continues until "high energy" processes such as quickly setting up physical barriers come into play, ending with full containment.

o Enablement and isolation of diverse protein reaction systems within the same cytosol medium.

The idea that in terms of interactions, molecules can both immediately reject and reject at low cost interactions not relevant to their purpose is another way of saying that even if a huge variety of molecules with very diverse purposes are distributed within the same cytosol, they can behave in effect as if they do not "see" any other molecules except the ones with which they are designed to react. These subnetworks thus can focus on their tasks with efficiency and relative impunity against cross-reactions.

There is a fascinating and I think rather important corollary to this idea of multi-scale enabled isolation of protein chemistry subnetworks, which is this: It only works if the proteins are pre-structured to stay isolated. That is, on average I would guess that high levels of mutual invisibility between protein reaction subnetworks is not likely, and that the subnetworks must in advance agree to certain "multi-scale protocols" about how to distinguish them from each other. This distinction would begin and be most critical at the largest and most efficient scales of charge blurring, the same levels that your paper abstract describes.

So, a prediction even: Careful analysis of the charge profiles of the many types of proteins found in eukaryotic (and prokaryotic, likely more accessible but not your main bailiwick) will reveal that multi-scale isolation of multiple subnetworks of interactions that are based first on high-level, "blurred" charge profiles between the proteins, with additional isolations at lower scales. It will be show statistically that the overall level of isolation between the subnetworks is extremely unlikely without all such reaction paths sharing the charge-profile equivalent of a registry in which each reaction subgroup has its own multi-scale "charge address".

o Possible insights into the protein folding problem.

Finally, it is worth noting that the hierarchical guidance concept that underlies biomolecular renormalization could well have relevance to the infamous multi-decade protein folding problem, which is this: How does a simple string of amino acids fold itself into a large and precisely functioning protein "machine"? This feat is roughly equivalent to a long chain of about twenty different link types somewhat magically folding itself into some form of complicated machine with moving parts.

Either directly through multi-scale attractions or indirectly through helper molecules, it is at least plausible that biomolecular renormalization may play a role in this folding process. With regard to helper molecules, one intriguing hypothesis (nothing more) is that previously folded proteins of that same type could provide some form of multi-scale guidance for how to fold new proteins.

While an intriguing idea, it is also frankly unlikely for the following reason: Such assistance would almost certainly require the existence of some class of "form transfer" helper molecules that would look at the existing molecules and from them find and present that information to the folding process. It is hard to imagine that such a system could exist and not have already been noticed.

Nonetheless, the concept of folding-begets-folding has an intriguing appeal from a simple information transfer perspective. And in one area it would resolve a very interesting resolution to a long-term mystery of large biomolecules, prions. Prions are proteins that have folded or refolded into destructive forms. Once established, these incorrectly folded proteins show a remarkable, even heretical ability to reproduce themselves by somehow "encouraging" correctly folded proteins to instead adopt the deleterious prion folding.

Folding-begets-folding would help to explain this mysterious process by making it a broken version of some inherent mechanism that cells have for reproducing the folding structures of proteins. Whether any of this is possible, and whether if so it is related to biomolecular renormalization, is an entirely open question.

Conclusions and Future Directions

As a concept, biomolecular renormalization appears to have good potential as a framework not only for understanding known and recently uncovered protein behaviors, but also to provide a more theory-based approach to designing proteins and enzymes. It may also provide insights into cell-level biological processes that previously have seemed opaque or mysterious under other forms of analysis.

To link to the above mini-essay, please copy and paste either of the following links:

[link:fqxi.org/community/forum/topic/3099#post_146380]Biomolecular Renormalization: A New Approach to Protein Chemistry[/link]

https://fqxi.org/community/forum/topic/3099#post_146380

Hi folks,

I've been so quiet that at least one FQXi community member was worried about me (which I really appreciated, incidentally).

For the last couple of months I've been working on a paper on special relativity (SR). While some of the ideas in it are ones I've been exploring for years, it was my need for a good reference paper relevant to several 2017 FQXi essays that provoked me to make completion of the paper a priority. The paper will have more explanatory graphics than most physics papers, since SR is an intensely geometric theory that requires good graphics to describe and explore properly. I'll provide status updates on the paper here.

I've been trying to practice what I advocated in my 2017 FQXi essay, Fundamental as Fewer Bits. Focusing on conciseness leads in turn to an assertion with which I think most physicists would agree in principle, but which can be surprisingly difficult to apply in practice:

Physics is both extremely efficient and minimally redundant.

It sounds reasonable, right? It is, after all, just a variant of Occam's Razor.

However, if you apply the above assertion to current physics in a ruthless, machine-logic-level, history-indifferent way, it can be devastating in deeply interesting ways. I'll leave it to the reader to wonder why and how.

Cheers, Terry Bollinger

Hi folks,

For anyone who is disappointed in not winning this year, and who may also have thought that my essay had a pretty good shot, don't feel too badly. The FQXi Essay Winners direct-contact announcement day has come and gone, and like most of you I didn't even get a mention.

That is of course disappointing. I really did think it was a pretty solid piece of work, enough so that I will most definitely use those ideas elsewhere. But the nice thing is that my involvement with all of you in this incredibly diverse community of off-the-beaten path thinkers was so stimulating that it helped me to look at my own years of private physics notes in new ways, and to develop a renewed enthusiasm for capturing certain recurring themes in the form of papers intended for journal publication. For that I thank all of you!

I will continue on occasion to post here notices about papers, ideas, or online postings of figures and such. It's possible but a bit unlikely that I may submit a new essay in some future FQXi Essay Contest. However, I think working towards getting published in appropriate journals is a better goal for me now, especially since I don't have much interest in the prize money part of this contest. FQXi questions are often delightfully inspiring, but perhaps that is the best way to view them: As personal research challenges, and not necessarily as part of a contest per se.

Finally, my sincere congratulations to whomever the winners for the contest were this year!

I have some personal favorites, but if you the winners are not whom I expected, I will focus all the more on reading your winning essays carefully to understand better your perspectives and insights.

Cheers, Terry

Giovanni,

It is good to hear from you again! Your essays and those you recommended (Coryat, Losev, Becker, and Bastiaansen I think it was), along with others (Tejinder Singh for example) were among that most helped me appreciate and to at least some degree better understand broader, more philosophical approaches to understanding reality. Given the paucity of answers that science has to offer even on why we are here at all, that is a humbling and valuable perspective.

In fact, the title of one of my planned mini-essays is Time, Life, and Awareness: A Physics Perspective. The only reason I have not completed and posted it is that I realized that I needed to complete a physics paper on the nature of time and time symmetries in special relativity to make my points about life and awareness more than just speculation. The nature of time is quite a bit different from most speculations about it, yet the arguments for how it really works are neither complicated nor easily dismissed once you frame the physics so as to avoid unnecessary redundancies and inefficiencies.

Our universe is almost unbelievably accommodating of inefficient theories, allowing (as Spekkens speculated in his 2012 FQXi essay) an incredibly diverse range of theories to predict the same results. Sharpening some of the classic arguments of special relativity to better address the causality that Spekkens postulated as a unifying principle can at the very least provide some insights. Remarkably, those insights are also relevant to understanding the deep relationship that living organisms have with time, and the inverse relationship of awareness that allows us to connect more directly with how the universe works.

That sounds like a highly abstract statement, but I assure you it is not: There is a very real, experimentally accessible difference between intelligence using only classical time, and intelligence focusing on causal state change as defined by the laws of all of physics. In that broader perspective, the use of classical time is an important but incomplete subset of how the universe changes state, a simplification necessary for surviving in the (very friendly overall) part of the universe in which we exist.

More later. Paper on causal symmetry in special relativity first!

Thank you also for the information on how the FQXi announcements work. I think the official date for posted announcements is May 8? In any case, for me it's all water under the bridge at this point, since I feel much happier assuming that it's all said and done, and so time to move on.

Cheers,

Terry

Hi Giovanni,

I think the American equivalent of "a stretto giro di posta", at least for older Americans like me, is "by FedEx", that is, by Federal Express. This phrase was used most often back when FedEx was the only company capable of shipping items overnight via their centralized receive-sort-ship facility in Memphis, Tennessee. The founder of FedEx, Frederick Smith, famously got an average-only grade when he first proposed this idea in a college paper.

You are exactly correct that space is different in a critical way from time, and that way is this: A space-only separation between two objects can always be made completely symmetric, while a time-only separation between two points (e.g. two images of the same object) can never be made fully symmetric due to one image always being farther back in time than the other.

That broken symmetry is saying something very important about the nature of time, which to be specific is that space is more fundamental than time, not less. Or to be more precise: Space-time symmetry is at its roots all about how objects in space change relative to each other, with time emerging as a result of that set of relationships. Thus in special relativity, the merger of space and time that Minkowski so delighted in (more so than Einstein at first) is due not to the independence of the two, but to the fact that time has no meaning at all without matter and energy changing state in space.

"Changing state" I should note is not the same thing as classical time, since classical time has an entire suite of precise and often space-like features that are narrower and more constrained than the concept of state change in isolation. Giving away a bit of my argument in Time, Life, Awareness: A Physics Perspective, this is also why less "scientific" practitioners of traditions that emphasize instantaneous sensor perception over history-based processing and interpretation of that sensory data are on to something non-trivial: They are recognizing that traditional classical time is far more of an in-your-head information processing construct than is generally realized, and that any full theory of how the universe changes state necessarily must extend beyond that model. I say "necessarily" because, trivially, neither classical not quantum concepts of time are sufficiently broad to enable full envelopment of how the universe actually works. Only a change model that enables classical and quantum time to emerge from a broader set of state change rules can suffice, and that model is, remarkably, a lot closer to instantaneous awareness than it is to ponderous (but also incredibly useful) entropic-based past-and-future perception and modeling of time.

This is of course delightfully in opposition to the views of a great many physicists, to whom the supremacy of time as reality is a psychologically paramount and simply not something to be questioned. But then again, that is exactly how you end up with both cultural and individual cognitive log jams: The very assumption that must be questioned in order to break the log jam seems so obvious, so fundamental, so sacred, that no person in that culture dares even to suggest otherwise.

Concerning that disregard, in my approach to physics I rely significantly on my involvement with new research directions in machine cognition, that is, with artificial intelligence. Good machine cognition is culturally oblivious in a way that is extraordinarily difficult for humans. Machines don't worry about what thesis advisors will think, or where funding will come from, or whether like the sad but brilliant Boltzmann they will be ostracized and driven to suicide by smart but vile geniuses like Mach. Instead, they worry about mathematical symmetries, data reduction, exploration paths, and heuristics for reducing the total search space. Machines don't forget or minimize those annoying dangling threads that have never been explained well. Instead, they place them at highest priority for both further exploration and path assessment, precisely because such unresolved issues are the gaps in the armor of existing theory that are most likely to lead to breakthroughs.

Again, good talking to you again, even though I will confess to doing a bit of a monologue from my side! I look forward to looking up your 2015 FQXi essay and reading it on Saturday, Cinco de Mayo. In the US this is a popular holiday for eating all types of Mexican food. Tacos and Time, a delicious dual delight!

Cheers,

Terry