Part number 1. Introduction to folding biology. From proteins to RNA
I must say right away that I will pose the question of bio-calculations from a certain cybernetics-geometric point of view. This is my name and this direction is not common. I am sure that it will be easier to understand for those who are not on the topic of this biological problem. Those who are already in the topic are ready to discuss with you and show why traditional methods are not suitable from the point of view of the cybernetic approach (but in this article you are not my audience - I'm sorry, but I’m sure it will be useful to you as an expansion of the world outlook on the problem).
The practical application for biologists has more to do with protein folding. To a certain extent, a lot of practical tasks can be reduced to this task (knowing how protein is folded), the main of which is the development of drugs to combat viruses and diseases.
But this problem in general has not been solved. These are like unsolved problems in mathematics, only with a biological context (see the Levintal paradox). Biologists can only with a certain error see through bioexperiments a state in an already minimized state, but it is not yet possible to trace how this happens. But all this is also very expensive. Why they do computer computing is cheap, even though thousands of computers are used in distributed projects.
But the introduction is enough, then from the ship to the ball ...
First, why is RNA, not protein? Just because it's easier. It is impossible to understand how proteins collapse without understanding how simpler RNA molecules fold. We are not biologists, and it is not the practical biological result that matters to us, but the understanding of the process mathematically / cybernetically.
Here is such a game FoldIt . And there is a reader’s question :
I answer. This game is a cry of despair . There are absolutely no algorithms that collapse. Even exhaustive search does not help. The Levintal paradox shows that the calculation of the folding of a molecule can last longer than the entire life of the Universe.
For players I propose such an experiment in the game. At first, you are given a molecule that is already somewhat convoluted and with some predetermined structure (spirals / sheets / loops). If you reset and load again, they will give you a slightly different structure and initial state. This initial state for you is already calculated by experts and simply distributes between you (as between computers) what you need to calculate. Do the following. Use the elastic bands to stretch the protein chain in a line. Remove all spirals and sheets from the structure, i.e. turn everything into a loop (actually just a chain without a structure). Before starting these steps, note how many points you were given (condition assessment). Compare with what happened. We see the difference is not very big. Right? But now try to collapse at least to the state that was originally. None of the available tools will help you do this automatically. If you do not remember how the structure looks approximately, you do not even have any hypotheses on how to do this. I would be glad if as David Baker says
but I'm a pessimist here.
Secondly, biologists like to talk about the minimum energy of folded protein, and supposedly when the energy is minimal - the protein occupies the most stable state. But this is not proven, it is a theory. This energy is influenced by a lot of factors that simply cannot be calculated.
But we will act in a completely different way. We will ONLY consider the importance of the formation of hydrogen bonds and the absence of forbidden covalent bonds (which I will explain later on). Why? Because in my experiments this was largely enough to get results comparable to the results of serious research projects (not quantitatively (since I have only one computer), but qualitatively).
And most importantly, we postulate this basic principle of the cybernetics-geometric approach:
Now a few pictures (by the way how to adjust the picture size, tell me who knows: it’s worth height = “20” width = “20” - but as you can see the size is large):
In the picture: step 0. We see the RNA chain. Whoever read my programmatically directed article is precisely the initial graph of the circuit in question.
Then you see how the chain in a few steps tends to curl into a spiral. A well-constructed spiral in the following figure.
So, I explain what covalent and hydrogen bonds are and for the first time is enough.
In step 0 (the first figure) - you see that the points are connected by lines. Points are individual atoms. And lines are allowed covalent bonds. During the folding process, it is impossible to allow any other covalent bonds to form, roughly speaking, so that the allowed covalent bonds intersect. In the FoldIt game, this is just shown by the red "rosehip" and is heavily fined by points. It’s just that in reality no such connections can be formed - there’s not enough energy for this, but of course it’s easy to wind up software so easily that it is easy to push. These are forbidden covalent bonds.
Hydrogen bonds are visible in the second figure red dashed lines between atoms. These bonds are more easily formed and basically they keep RNA in a folded state.
In the second part, we will talk about what hydrogen bonds are, how to describe their formation mathematically and the initial steps to how to start folding RNA. But I would like feedback - write, who understood what, and whether you are ready to read the second part . Or I missed something for understanding, it will only be more difficult further, therefore it is better to speak right away.
The practical application for biologists has more to do with protein folding. To a certain extent, a lot of practical tasks can be reduced to this task (knowing how protein is folded), the main of which is the development of drugs to combat viruses and diseases.
But this problem in general has not been solved. These are like unsolved problems in mathematics, only with a biological context (see the Levintal paradox). Biologists can only with a certain error see through bioexperiments a state in an already minimized state, but it is not yet possible to trace how this happens. But all this is also very expensive. Why they do computer computing is cheap, even though thousands of computers are used in distributed projects.
But the introduction is enough, then from the ship to the ball ...
First, why is RNA, not protein? Just because it's easier. It is impossible to understand how proteins collapse without understanding how simpler RNA molecules fold. We are not biologists, and it is not the practical biological result that matters to us, but the understanding of the process mathematically / cybernetically.
Here is such a game FoldIt . And there is a reader’s question :
I did not quite understand how manual exhaustion reduces modeling by an order of magnitude. The fact that people roll protein with their hands is also generally random, because people don’t even approximately understand how to fold it. And if we assume that people simply discard a number of unrealistic options for some reason, why can’t this be algorithmized in folding @ home?
I answer. This game is a cry of despair . There are absolutely no algorithms that collapse. Even exhaustive search does not help. The Levintal paradox shows that the calculation of the folding of a molecule can last longer than the entire life of the Universe.
For players I propose such an experiment in the game. At first, you are given a molecule that is already somewhat convoluted and with some predetermined structure (spirals / sheets / loops). If you reset and load again, they will give you a slightly different structure and initial state. This initial state for you is already calculated by experts and simply distributes between you (as between computers) what you need to calculate. Do the following. Use the elastic bands to stretch the protein chain in a line. Remove all spirals and sheets from the structure, i.e. turn everything into a loop (actually just a chain without a structure). Before starting these steps, note how many points you were given (condition assessment). Compare with what happened. We see the difference is not very big. Right? But now try to collapse at least to the state that was originally. None of the available tools will help you do this automatically. If you do not remember how the structure looks approximately, you do not even have any hypotheses on how to do this. I would be glad if as David Baker says
sincerely believes that somewhere in the world there are talents who have the innate ability to calculate 3D models of proteins in the mind. Some 12-year-old boy from Indonesia will see the game and be able to solve problems that even a supercomputer cannot do
but I'm a pessimist here.
Secondly, biologists like to talk about the minimum energy of folded protein, and supposedly when the energy is minimal - the protein occupies the most stable state. But this is not proven, it is a theory. This energy is influenced by a lot of factors that simply cannot be calculated.
But we will act in a completely different way. We will ONLY consider the importance of the formation of hydrogen bonds and the absence of forbidden covalent bonds (which I will explain later on). Why? Because in my experiments this was largely enough to get results comparable to the results of serious research projects (not quantitatively (since I have only one computer), but qualitatively).
And most importantly, we postulate this basic principle of the cybernetics-geometric approach:
we idealize the folding process without considering any other interactions other than hydrogen bonds. Thus, in modeling, we deliberately proceed from simplification, idealization, as if answering the questions: “how will the folding process go if RNA strives only to form hydrogen bonds?” And “what is the“ pure ”contribution of the formation of hydrogen bonds to the folding process? "(This is from my scientific article)
Now a few pictures (by the way how to adjust the picture size, tell me who knows: it’s worth height = “20” width = “20” - but as you can see the size is large):
In the picture: step 0. We see the RNA chain. Whoever read my programmatically directed article is precisely the initial graph of the circuit in question.
Then you see how the chain in a few steps tends to curl into a spiral. A well-constructed spiral in the following figure.
So, I explain what covalent and hydrogen bonds are and for the first time is enough.
In step 0 (the first figure) - you see that the points are connected by lines. Points are individual atoms. And lines are allowed covalent bonds. During the folding process, it is impossible to allow any other covalent bonds to form, roughly speaking, so that the allowed covalent bonds intersect. In the FoldIt game, this is just shown by the red "rosehip" and is heavily fined by points. It’s just that in reality no such connections can be formed - there’s not enough energy for this, but of course it’s easy to wind up software so easily that it is easy to push. These are forbidden covalent bonds.
Hydrogen bonds are visible in the second figure red dashed lines between atoms. These bonds are more easily formed and basically they keep RNA in a folded state.
In the second part, we will talk about what hydrogen bonds are, how to describe their formation mathematically and the initial steps to how to start folding RNA. But I would like feedback - write, who understood what, and whether you are ready to read the second part . Or I missed something for understanding, it will only be more difficult further, therefore it is better to speak right away.