Principles that Govern the Folding of Protein Chains
20 Jul 1973-Science (American Association for the Advancement of Science)-Vol. 181, Iss: 4096, pp 223-230
TL;DR: Anfinsen as discussed by the authors provided a sketch of the rich history of research that provided the foundation for his work on protein folding and the Thermodynamic Hypothesis, and outlined potential avenues of current and future scientific exploration.
Abstract: Stanford Moore, William Stein, and Anfinsen were awarded the Nobel Prize in Chemistry in 1972 for \"their contribution
to the understanding of the connection between chemical structure and catalytic activity of the active center of the ribonuclease
molecule.\" In his Nobel Lecture, Anfinsen provided a sketch of the rich history of research that provided the foundation
for his work on protein folding and the \"Thermodynamic Hypothesis,\" and outlined potential avenues of current and
future scientific exploration.
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TL;DR: A computer program that progressively evaluates the hydrophilicity and hydrophobicity of a protein along its amino acid sequence has been devised and its simplicity and its graphic nature make it a very useful tool for the evaluation of protein structures.
21,921 citations
TL;DR: For example, AlphaFold as mentioned in this paper predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture. But the accuracy is limited by the fact that no homologous structure is available.
Abstract: Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort1–4, the structures of around 100,000 unique proteins have been determined5, but this represents a small fraction of the billions of known protein sequences6,7. Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’8—has been an important open research problem for more than 50 years9. Despite recent progress10–14, existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14)15, demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm. AlphaFold predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture.
10,601 citations
4,643 citations
TL;DR: Folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.
Abstract: In the cell, as in vitro, the final conformation of a protein is determined by its amino-acid sequence. But whereas some isolated proteins can be denatured and refolded in vitro in the absence of other macromolecular cellular components, folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.
4,181 citations
TL;DR: The present review aims to provide a reassessment of the factors important for folding in light of current knowledge, including contributions to the free energy of folding arising from electrostatics, hydrogen-bonding and van der Waals interactions, intrinsic propensities, and hydrophobic interactions.
Abstract: T e purpose of this review is to assess the nature and magnitudes of the dominant forces in protein folding. Since proteins are only marginally stable at room temperature,’ no type of molecular interaction is unimportant, and even small interactions can contribute significantly (positively or negatively) to stability (Alber, 1989a,b; Matthews, 1987a,b). However, the present review aims to identify only the largest forces that lead to the structural features of globular proteins: their extraordinary compactness, their core of nonpolar residues, and their considerable amounts of internal architecture. This review explores contributions to the free energy of folding arising from electrostatics (classical charge repulsions and ion pairing), hydrogen-bonding and van der Waals interactions, intrinsic propensities, and hydrophobic interactions. An earlier review by Kauzmann (1959) introduced the importance of hydrophobic interactions. His insights were particularly remarkable considering that he did not have the benefit of known protein structures, model studies, high-resolution calorimetry, mutational methods, or force-field or statistical mechanical results. The present review aims to provide a reassessment of the factors important for folding in light of current knowledge. Also considered here are the opposing forces, conformational entropy and electrostatics. The process of protein folding has been known for about 60 years. In 1902, Emil Fischer and Franz Hofmeister independently concluded that proteins were chains of covalently linked amino acids (Haschemeyer & Haschemeyer, 1973) but deeper understanding of protein structure and conformational change was hindered because of the difficulty in finding conditions for solubilization. Chick and Martin (191 1) were the first to discover the process of denaturation and to distinguish it from the process of aggregation. By 1925, the denaturation process was considered to be either hydrolysis of the peptide bond (Wu & Wu, 1925; Anson & Mirsky, 1925) or dehydration of the protein (Robertson, 1918). The view that protein denaturation was an unfolding process was
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References
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1,488 citations
TL;DR: There existed a considerable lag phase before enzymatic activity appeared after the sample of bovine pancreatic ribonuclease was treated with mercaptoethanol in urea, during which period the sulfhydrl titer and the specific optical rotation changed along a curve similar to that of a first-order reaction.
Abstract: In this article, Anfinsen, Haber, Sela, and White reported that there existed a considerable lag phase before enzymatic activity
appeared after the sample of bovine pancreatic ribonuclease was treated with mercaptoethanol in urea, during which period
the sulfhydrl titer and the specific optical rotation changed along a curve similar to that of a first-order reaction. The
lag in enzymatic activity in vitro often took several hours, while the same process seemed to take only a few minutes in vivo.
This discrepancy eventually led to the discovery of an enzyme system in the endoplasmic reticulum of cells that catalyzes
the disulfide interchange reaction, and subsequently, the rapid formation of the correct, native disulfide pairing in relatively
short order.
1,113 citations
824 citations
TL;DR: In a protein of unknown structure, a regular periodicity of invariant non-polar sites might serve to recognize helical regions, and the incidence of prolines to define their lengths, if all the proline sites observed are plotted along the sequence.
580 citations
TL;DR: It was noted that difficulties can be encountered particularly in the determination of sequences of peptides containing glutamine, asparagine, serine, and threonine residues and a new examination of the amino acid sequence of the whole molecule was stimulated to determine whether such complications had affected any of the conclusions drawn in regard to other parts of the chain.
524 citations