protein folding

The process by which a protein acquires its functional structure and conformation

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protein Protein folding is a process in which proteins obtain their functional structure and conformation. Through this physical process , protein from Irregular crimp Collapse into specific functionality three-dimensional structure 。 From mRNA Sequence translated into linear Peptide chain Protein exists in the form of unfolded polypeptide or irregular curl.

In 2023, Japanese scientists have discovered a series of previously unknown protein folding.^[1]

Chinese name: protein folding
Basic unit: amino acid

Features: Hydrophilicity 、 Hydrophobicity , with positive electricity
theoretical model: Frame model , hydrophobic collapse model, etc

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preface

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Protein folding. Source: bitjoy net.png

Structure determines function. Just knowing the genome sequence can not make us fully understand the function of protein, let alone how it works. Proteins can interact in the cell environment (specific PH , temperature, etc.), which is called protein folding.

Protein folding is listed as "the 21st century Biophysics ”It is an important subject of molecular biology Central rule A major unsolved biological problem. Prediction of protein molecular structure from primary sequence Tertiary structure It is a challenging task to further predict its functions. The study of protein folding, especially the early process of folding, that is, the folding process of new peptide segments, is a fundamental problem to comprehensively clarify the central rule. In this field, recent discoveries have fundamentally revised the traditional concept that new peptide segments can be folded spontaneously. Among them, X-ray Crystal diffraction And various spectrum Technology and electron microscope Technology has played an extremely important role. The 13th session International Conference on Biophysics Ernst, Nobel Prize winner, emphasized in his report that, NMR One of the main advantages of studying proteins is that it can study the dynamics of protein molecules in great detail, that is, the relationship between dynamic structure or structural movement and protein molecular function. The current NMR technology has been able to picosecond Observation in time domain of protein structure The movement process of, including the main chain and Side chain And protein folding and unfolding under various temperatures and pressures. protein macromolecule Of structural analysis It is not only to solve a specific structure, but also to pay more attention to the fluctuation and movement of the structure. For example, enzymes and proteins that transport small molecules usually have two conformations ligand And unbound ligand. The structural fluctuation within a conformation is the necessary prelude to the conformational transformation, so it is necessary to spectroscopy ， Spectroscopy Combine with X-ray structure analysis to study the balance of structural fluctuations, conformational changes and various forms formed in the process of change Intermediate state For another example, in order to understand how proteins fold, it is necessary to know several basic processes of protein folding time scale And mechanisms, including Secondary structure (Spiral and fold) formation, curling, long-range interactions, and total collapse of unfolded peptides. Multiple technologies are used to study secondary processes, such as fast nuclear magnetic resonance , rapid spectroscopy (fluorescence, far ultraviolet and Near ultraviolet Circular dichroism).

Research overview

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In organisms, Bioinformation The flow of can be divided into two parts: the first part is stored in DNA sequence In genetic information It is the transmission of one-dimensional information into the primary sequence of the protein through transcription and translation, and the triplet code mediates this Transfer process ； The second part is Peptide chain After hydrophobic collapse, space curl Side chain Aggregation and other folding processes form the natural conformation of protein, and obtain biological activity To express life information; Protein is the life information expression vector , the specific space structure It is the basis of its biological function, that is to say, the transformation process from one-dimensional information to three-dimensional information is necessary to show the vitality of life.

Since the 1960s, Anfinsen has been based on reduced and denatured bovine pancreas RNase Without any other Material help Lower, only by removing Denaturant and reducing agent On the basis of the experimental results of restoring its natural structure, the author proposed that Peptide chain Of amino acid The sequence consists of thermodynamics All information necessary for stable natural conformation“ Self-assembly theory ”Since then, with the extensive development of protein folding research, people have further supplemented and expanded the theory of protein folding. Anfinsen's "Thermodynamic Hypothesis of Self assembly" has gained a lot In vitro experiment It is proved that many proteins can undergo reversible denaturation and Renaturation , especially some small molecular weight proteins, but not all proteins are the same. And because of the special environmental factor The protein folding in the body is far from the same.

Protein folding in the body often requires other Cofactor With ATP Hydrolysis of. Therefore, Ellis proposed the "auxiliary assembly theory" of protein folding in 1987. This shows that protein folding is not just a thermodynamics It is obvious that the process of is also controlled by dynamics. Some scholars based on some similarities amino acid The sequence of proteins has different Folding structure However, some other proteins with different amino acid sequences are similar in structure, suggesting that mRNA Secondary structure Maybe as a Genetic code Thus affecting protein structure Hypothesis. But so far, there is no experimental evidence for this hypothesis, only some pure mathematical arguments [3]. So, how does the amino acid sequence of a protein determine its spatial conformation? Around this issue Scientific researchers A lot of excellent work has been done, but so far our understanding of protein folding mechanism is still incomplete, and even some aspects still have wrong views.

A typical example of research that has made important contributions in this regard is C B. Amphenson Group About RNase I Denaturation and Renaturation Research. There are 124 bovine pancreatic ribonucleases Amino acid residue , consisting of 8 Mercapto group Pairing to form 4 pairs Disulfide bond 。 It can be calculated that there are 105 possible ways in which eight sulfhydryl groups in the enzyme molecule form four disulfide bonds, which provides a quantitative index for estimating refolding recombination. Under mild alkaline conditions, 8 mole Of concentrated urea and a large amount of Mercaptoethanol It can completely reduce four pairs of disulfide bonds, and the whole molecule becomes Irregular crimp And denaturation of enzyme molecules. The urea is removed by dialysis. In the presence of oxygen, the disulfide bond is formed again, and the enzyme molecule is completely Renaturation The paired sulfhydryl groups in disulfide bonds are the same as those in nature. The refolded molecules can be crystallized and have crystal The same X-ray diffraction pattern confirmed that the enzyme molecule could not only refold spontaneously, but only chose one of 105 possible disulfide bond pairing modes during refolding.

In 2023, Japanese scientists discovered a series of previously unknown protein folding.^[1]

Japanese scientists have discovered a series of previously unknown protein folding

theoretical model

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Frame model

（Framework Model）

Frame model [4] It is assumed that the local conformation of the protein depends on the local amino acid Sequence. stay Polypeptide chain In the initial stage of the folding process, unstable Secondary structure Unit; It is called "flicking cluster", and then these secondary structures are close to each other to form a stable secondary structure framework; Finally, the secondary structural frames are spliced together, Peptide chain Gradually shrink, forming the tertiary structure of protein. This model believes that even a Small molecule The protein can also be folded part by part, and the sub domain formed in it is an important structure of folding intermediates.

Collapse model

（Hydrophobic Collapse Model）

In the hydrophobic collapse model [5], hydrophobic Force It is considered to be a decisive factor in protein folding. After forming any Secondary structure and Tertiary structure Before that, fast nonspecific hydrophobic collapse occurred first.

Adhesion mechanism

（Diffusion-Collision-Adhesion Model）

This model believes that protein folding starts from stretching Peptide chain Several sites on which unstable Secondary structure Unit or hydrophobic cluster, mainly depending on the process of local sequence or Medium range (3-4 Residue ）Interaction to maintain. They are nonspecific Brownian motion The way of diffusion, collision and mutual adhesion leads to the formation of large structures and thus increases the stability. Further collision forms a class with hydrophobic core and secondary structure Molten spheroid state Spherical structure of intermediate. The spherical intermediate is adjusted to a dense, inactive, highly ordered molten spheroidal structure similar to the natural structure. Finally, the inactive highly ordered molten ball state is transformed into a complete and active natural state.

growth model

（Nuclear-Condensation-Growth Model）

According to this model, Peptide chain An area in the can form a "fold Crystal nucleus ”With them as the core, the whole peptide chain continues to fold to obtain a natural conformation. The so-called "crystal nucleus" is actually composed of some special Amino acid residue Formed similar to natural state interaction network structure These residues are not nonspecific Hydrophobic action It is maintained by the specific interaction that makes these residues form a tight stack. Nucleus formation is the initial stage of folding Speed limit steps 。

Mosaic model

（Jig-Saw Puzzle Model）

The central idea of this model [9] is Polypeptide chain It can be folded along many different paths. In the process of folding along each path, there are more and more natural structures, which can eventually form a natural conformation. In addition, the folding speed along each path is faster, which is more than that of a single path Peptide chain The speed is fast. On the other hand, small changes or mutations in the external physiological and biochemical environment may have a greater impact on a single folding path. For folding methods with multiple paths, these changes may have an impact on one folding path, but will not affect another, so they will not interfere with the folding of polypeptide chains in general, Unless the changes caused by these factors are too large to fundamentally affect the folding of polypeptide chains.

Lattice model

Lattice point The model (also referred to as HP model) was first proposed by Dill et al. in 1989. The lattice model can be divided into 2D model and three-dimensional model Two types. The two-dimensional grid point model is orthogonal in the plane space Unit length 's grid, each amino acid Molecules are placed on these grid intersections in sequence. When adjacent amino acid molecules in the sequence are placed in the grid, they must also be adjacent, that is, the distance between adjacent amino acid molecules in the grid model is 1. However, it should be noted that each intersection in the grid can only place one amino acid molecule at most. If an amino acid molecule in the sequence has been placed at this position Postorder The amino acid molecule of can no longer be placed on this grid point. If there is no place for the amino acid molecule to be placed during the placement of amino acid molecules, it means that the configuration is unreasonable and needs to be relocated. The 3D grid model is similar to the 2D grid model three-dimensional space The solid mesh per unit length generated in. Place in grid point amino acid The molecular method is the same as that of two-dimensional, but when placing amino acid molecules in two-dimensional grid model, there are only three directions to choose at most except for the first two amino acid molecules in the sequence, while in three-dimensional grid model, the complexity has been improved a lot, and there are at most five directions to choose when placing amino acid molecules.

Molecular chaperone

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In 1978, Laskey Histone and DNA In vitro physiology ionic strength It was found during the experiment that there must be nucleus In the presence of the acidic protein nucleoplasmin, they can be assembled into Nucleosome Otherwise, sedimentation will occur. So Laskey calls it“ Molecular chaperone ”。 Molecular chaperone refers to the ability to bind and stabilize the unstable conformation of another protein, and to promote newborn through controlled binding and release Polypeptide chain Fold POLYMER Assembly or degradation and Organelle A class of proteins involved in transmembrane transport of proteins [10,11]. Molecular chaperone is defined from the function. All proteins with this function are molecular chaperones, and their structures can be completely different. This concept has been extended to many proteins, and the molecular chaperones identified now mainly belong to three types of highly conservative Protein family [12]：stress 90 family、stress 70 family、stress 60 family。 The stress 60 family exists in Eukaryote Of mitochondrion (on mammal Called Hsp58 in) chloroplast (called cpn60), in the prokaryote Of cytoplasm It is called GroEL.

significance

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The elucidation of protein folding mechanism will reveal the second set in life Genetic code This is its theoretical significance. The narrow definition of protein folding is to study protein specific three-dimensional space The regularity and stability of structure formation biological activity Relationship. Conceptually thermodynamics The problem of dynamics; Protein folding in vitro and in cells; Theoretical research and experimental study Problems. Here's the most fundamental scientific problems namely Polypeptide chain How does its primary structure determine its spatial structure? Since the former determines the latter, there must be a certain relationship between the primary structure and the spatial structure nucleotide Via“ Triple password ”Decision amino acid Is there a set of passwords in that order? Some people call the password that the primary structure determines the spatial structure "the second genetic code".

If the "triple code" has been deciphered but has actually become clear code, then decipher the "second Genetic code ”Exactly“ protein structure Prediction is the most direct way to solve the problem of protein folding in theory, which is one of the last mysteries of protein research that has not yet been revealed. “ Protein structure prediction ”Theoretical thermodynamics Question. It is to predict the specific spatial structure determined by the Anfinsen principle according to the measured protein primary sequence. The amino acid sequence of a protein, especially one that encodes proteins nucleotide sequence The determination of DNA has now become almost routine technology, from complementary DNA（ cDNA ）The sequence can be based on“ Triple password ”The deduced amino acid sequence, which has made great breakthrough in the last century Molecular Biology Technology , greatly accelerated Primary structure of protein Determination of. at present Protein database The primary structure of about 170000 proteins has been stored in, but only about 12000 proteins have been measured for spatial structure, many of which are very similar Homologous protein There are only more than 1000 different proteins. along with human genome project The successful completion of, has interpreted the entire sequence of human DNA, the growth of protein primary structure data will inevitably explode, and the speed of spatial structure measurement is far behind, so there will be a greater distance between the two, which needs more protein structure Forecast of.

prospect

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At the same time, it also has important potential application prospects, such as the following aspects:

Renaturation of inclusion body

▲ Use DNA recombination technology You can set Foreign gene introduction host cell 。 However, the expression products of recombinant genes often form inactive and insoluble inclusion body 。 The clarification of folding mechanism will be of great help to the renaturation of inclusion bodies.

protein

▲ DNA recombination and Polypeptide synthesis The development of technology enables us to design long Polypeptide chain 。 However, because we cannot understand what kind of conformation this polypeptide will fold, we cannot design the protein we need with specific functions according to our own wishes.

Pathogenesis

▲ Many diseases, such as Alzheimer's disease （Alzheimer's）， Mad cow disease (Mad Cow, BSE ）, transmissibility Spongiform encephalopathy (CJD), Muscle Atrophic lateral sclerosis （ ALS ）And Parkinson's disease, which is caused by the mutation of some important proteins in cells Coalescence precipitation Or wrong folding. Therefore, an in-depth understanding of the relationship between protein folding and misfolding will be of great help to the elucidation of the pathogenesis of these diseases and the search for treatment methods.

Revealing function

▲ The development of genome sequence has enabled us to obtain a large number of protein sequences, and the acquisition of structural information is very important to reveal their biological functions. Rely on existing means (X-ray crystal diffraction NMR It takes a long time to determine the protein structure, so the pace of structure analysis has lagged behind the pace of discovering new proteins. Although the method of structural prediction is fast, its reliability is not high protein structure Only when the physical and chemical factors driving protein folding are better understood can this method be fundamentally improved. In addition, we are interested in the interaction between proteins ligand Interaction with protein Isostructure And Functional relationship The research of protein folding also depends on the elucidation of protein folding mechanism.

Folding disease

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Protein molecular amino acid The sequence does not change, but its structure or conformation changes can also cause disease, which is called“ Conformational disease ”, or "folding disease".

Mad cow disease from Prion It is caused by the infection of protein, which can also infect people Nervous system diseases 。 In the normal body, Prion is a protein required for normal neural activity, and the disease causing Prion and normal Prion Primary structure Identical, but different in spatial structure.

The diseases caused by the abnormal folding of proteins that result in molecular aggregation or even precipitation or can not be transported in place normally are senile dementia , cystic fibrosis, familial hypercholesterolemia, familial amyloidosis, some tumour 、 cataract wait.

because Molecular chaperone It plays an important role in protein folding. Mutation of molecular chaperone itself will obviously cause abnormal protein folding and cause folding disease. With the deepening of protein folding research, scientists will find the true causes of more diseases and more targeted treatment methods, and design more effective drugs.

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