Protein Folding

Extracted Attributes

• Outcome

  Biologically functional or active protein (native state).

• Definition

  The physical process by which a protein, after synthesis as a linear chain of amino acids, changes from an unstable random coil into a more ordered, stable, three-dimensional structure.

• Determinant

  Amino acid sequence (primary structure).

• Start Point

  Often begins co-translationally (during the translation of the polypeptide chain).

• Thermodynamics

  Spontaneous process under suitable physiological conditions, thermodynamically favorable (negative Gibbs free energy).

• Key Interactions

  Hydrophobic interactions, intramolecular hydrogen bonds, van der Waals forces, disulfide bonds.

• Folding Time Scale

  Varies from microseconds (small single-domain proteins, fastest known) to minutes or hours (slowest proteins, often due to proline isomerization).

• Computational Challenge

  Has been an important challenge for computational biology since the late 1960s.

• Consequences of Misfolding

  Inactive proteins, modified or toxic functionality, accumulation of amyloid fibrils, prions, neurodegenerative diseases, allergies.

• Factors Influencing Folding Time

  Size, contact order, circuit topology.

Timeline

• Understanding and simulating protein folding became an important challenge for computational biology. (Source: summary)

  1960s

• Christian Anfinsen's experiments demonstrated that denatured RNase can spontaneously refold in vitro to its active form, establishing the principle that amino acid sequence contains all information for folding. Levinthal's paradox was also proposed. (Source: web_search_results)

  1968

• DeepMind's AlphaFold AI system, developed by Demis Hassabis and John Jumper, achieved a significant breakthrough in solving the protein folding problem, leading to a Nobel Prize for its developers. (Source: summary, related_documents)

  Recent

Protein folding

Protein folding is the physical process by which a protein, after synthesis by a ribosome as a linear chain of amino acids, changes from an unstable random coil into a more ordered three-dimensional structure. This structure permits the protein to become biologically functional or active. The folding of many proteins begins even during the translation of the polypeptide chain. The amino acids interact with each other to produce a well-defined three-dimensional structure, known as the protein's native state. This structure is determined by the amino-acid sequence or primary structure. The correct three-dimensional structure is essential to function, although some parts of functional proteins may remain unfolded, indicating that protein dynamics are important. Failure to fold into a native structure generally produces inactive proteins, but in some instances, misfolded proteins have modified or toxic functionality. Several neurodegenerative and other diseases are believed to result from the accumulation of amyloid fibrils formed by misfolded proteins, the infectious varieties of which are known as prions. Many allergies are caused by the incorrect folding of some proteins because the immune system does not produce the antibodies for certain protein structures. Denaturation of proteins is a process of transition from a folded to an unfolded state. It happens in cooking, burns, proteinopathies, and other contexts. Residual structure present, if any, in the supposedly unfolded state may form a folding initiation site and guide the subsequent folding reactions. The duration of the folding process varies dramatically depending on the protein of interest. When studied outside the cell, the slowest folding proteins require many minutes or hours to fold, primarily due to proline isomerization, and must pass through a number of intermediate states, like checkpoints, before the process is complete. On the other hand, very small single-domain proteins with lengths of up to a hundred amino acids typically fold in a single step. Time scales of milliseconds are the norm, and the fastest known protein folding reactions are complete within a few microseconds. The folding time scale of a protein depends on its size, contact order, and circuit topology. Understanding and simulating the protein folding process has been an important challenge for computational biology since the late 1960s.

Web Search Results

• Protein Folding - an overview

  Protein folding is an intricate and precise process in living cells. Most exported proteins evade cytoplasmic folding, become targeted to the membrane, and then trafficked into/across membranes. Their targeting and translocation-competent states are nonnatively folded. However, once they reach the appropriate cellular compartment, they can fold to their native states. The nonnative states of preproteins remain structurally poorly characterized since increased disorder, protein sizes, [...] Protein folding is a spontaneous process under suitable physiological conditions and is determined mainly by its amino acid sequence. Understanding this complex process will therefore provide a unique insight into the way in which evolutionary selection has influenced the properties of a molecular system for functional advantage. The tendency of a polypeptide chain with proper primary structure to fold into its native form, without external help, completes the vital link in the series leading [...] The process of protein folding is a notoriously complicated process. For proteins containing disulfide bonds, it is a combination of two distinct, but interrelated processes: conformational folding of the protein sequence into secondary and tertiary structures and formation of disulfide bonds. By taking advantage of the relatively slow kinetics in disulfide bond formation, the Tan group was able to confirm the importance of glycosylation in regulating the folding of a family 1

• Protein folding

  Folding is a spontaneous process that is mainly guided by hydrophobic interactions, formation of intramolecular hydrogen bonds, van der Waals forces, and it is opposed by conformational entropy. The folding time scale of an isolated protein depends on its size, contact order, and circuit topology. Inside cells, the process of folding often begins co-translationally "Translation (genetics)"), so that the N-terminus of the protein begins to fold while the C-terminal portion of the protein is [...] Dual polarisation interferometry is a surface-based technique for measuring the optical properties of molecular layers. When used to characterize protein folding, it measures the conformation by determining the overall size of a monolayer of the protein and its density in real time at sub-Angstrom resolution, although real-time measurement of the kinetics of protein folding are limited to processes that occur slower than ~10 Hz. Similar to circular dichroism, the stimulus for folding can be a [...] Protein folding must be thermodynamically favorable within a cell in order for it to be a spontaneous reaction. Since it is known that protein folding is a spontaneous reaction, then it must assume a negative Gibbs free energy value. Gibbs free energy in protein folding is directly related to enthalpy and entropy. For a negative delta G to arise and for protein folding to become thermodynamically favorable, then either enthalpy, entropy, or both terms must be favorable.

• Protein Folding

  Protein Folding --------------- Proteins are folded and held together by several forms of molecular interactions. The molecular interactions include the thermodynamic stability of the complex, the hydrophobic interactions and the disulfide bonds formed in the proteins. The figure below (Figure \\(\\PageIndex{2}\\)) is an example of protein folding. Image 11: 20120922030628!Protein_folding.png Figure \\(\\PageIndex{2}\\): Protein Folding. (Public Domain; DrKjaergaard via Wikipedia) [...] \\( \\newcommand{\\inner}\[2\]{\\langle #1, #2 \\rangle}\\) \\( \\newcommand{\\Span}{\\mathrm{span}}\\) \\( \\newcommand{\\AA}{\\unicode\[.8,0\]{x212B}}\\) \\( \\newcommand{\\vectorA}\[1\]{\\vec{#1}} % arrow\\) \\( \\newcommand{\\vectorAt}\[1\]{\\vec{\\text{#1}}} % arrow\\) \\( \\newcommand{\\vectorB}\[1\]{\\overset { \\scriptstyle \\rightharpoonup} {\\mathbf{#1}} } \\) \\( \\newcommand{\\vectorC}\[1\]{\\textbf{#1}} \\) \\( \\newcommand{\\vectorD}\[1\]{\\overrightarrow{#1}} \\) [...] \\( \\newcommand{\\inner}\[2\]{\\langle #1, #2 \\rangle}\\) \\( \\newcommand{\\Span}{\\mathrm{span}}\\) \\( \\newcommand{\\id}{\\mathrm{id}}\\) \\( \\newcommand{\\Span}{\\mathrm{span}}\\) \\( \\newcommand{\\kernel}{\\mathrm{null}\\,}\\) \\( \\newcommand{\\range}{\\mathrm{range}\\,}\\) \\( \\newcommand{\\RealPart}{\\mathrm{Re}}\\) \\( \\newcommand{\\ImaginaryPart}{\\mathrm{Im}}\\) \\( \\newcommand{\\Argument}{\\mathrm{Arg}}\\) \\( \\newcommand{\\norm}\[1\]{\\| #1 \\|}\\)

• Protein Folding and Processing - The Cell

  protein folding takes place, yielding a protein correctly folded into its functional three-dimensional conformation. Members of the Hsp70 and Hsp60 families are found in the cytosol and in subcellular organelles (e.g., mitochondria) of eukaryotic cells, as well as in bacteria (see Table 7.2), so the sequential action of Hsp70 and Hsp60 appears to represent a general pathway of protein folding. An alternative pathway for the folding of some proteins in the cytosol and endoplasmic reticulum may [...] conformation (see Figure 2.17). Protein folding thus appeared to be a self-assembly process that did not require additional cellular factors. More recent studies, however, have shown that this is not an adequate description of protein folding within the cell. The proper folding of proteins within cells is mediated by the activities of other proteins. [...] The three-dimensional conformations of proteins result from interactions between the side chains of their constituent amino acids, as reviewed in Chapter 2. The classic principle of protein folding is that all the information required for a protein to adopt the correct three-dimensional conformation is provided by its amino acid sequence. This was initially established by Christian Anfinsen’s experiments demonstrating that denatured RNase can spontaneously refold _in vitro_ to its active

• Protein Misfolding and Degenerative Diseases

  squiggly line, is exiting the ribosome and entering the ER through the pore. After the protein enters the ER lumen, it can follow two pathways to different destinations in the cell, depending on whether it is folded correctly or misfolded. A correctly folded protein is shown entering a budding vesicle at the bottom edge of the ER, where it will be transported to the Golgi apparatus. A misfolded protein is exported from the ER to the cytosol where it is degraded by the ubiquitin-proteasome [...] As Anfinsen demonstrated, the information needed for proteins to fold in their correct minimal-energy configuration is coded in the physicochemical properties of their amino acid sequence. Usually a protein is capable of finding its functional or native state just by itself, in a matter of microseconds. The concept of how proteins explore the enormous structural conformational space is known as Levinthal's paradox. In 1968, Levinthal proposed that a protein folds rapidly because its constituent [...] As discussed already, misfolded proteins result when a protein follows the wrong folding pathway or energy-minimizing funnel, and misfolding can happen spontaneously. Most of the time, only the native conformation is produced in the cell. But as millions and millions of copies of each protein are made during our lifetimes, sometimes a random event occurs and one of these molecules follows the wrong path, changing into a toxic configuration. This kind of conformational change is most likely to