Protein tertiary structure is the three-dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains and the backbone may interact and bond in a number of ways. The interactions and bonds of side chains within a particular protein determine its tertiary structure. The protein tertiary structure is defined by its atomic coordinates. These coordinates may refer either to a protein domain or to the entire tertiary structure. A number of these structures may bind to each other, forming a quaternary structure.
Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure. Structure prediction is different from the inverse problem of protein design. Protein structure prediction is one of the most important goals pursued by computational biology; it is important in medicine and biotechnology.
Critical Assessment of Structure Prediction (CASP), sometimes called Critical Assessment of Protein Structure Prediction, is a community-wide, worldwide experiment for protein structure prediction taking place every two years since 1994. CASP provides research groups with an opportunity to objectively test their structure prediction methods and delivers an independent assessment of the state of the art in protein structure modeling to the research community and software users. Even though the primary goal of CASP is to help advance the methods of identifying protein three-dimensional structure from its amino acid sequence many view the experiment more as a “world championship” in this field of science. More than 100 research groups from all over the world participate in CASP on a regular basis and it is not uncommon for entire groups to suspend their other research for months while they focus on getting their servers ready for the experiment and on performing the detailed predictions.
Predictor@home was a volunteer computing project that used BOINC software to predict protein structure from protein sequence in the context of the 6th biannual CASP, or Critical Assessment of Techniques for Protein Structure Prediction. A major goal of the project was the testing and evaluating of new algorithms to predict both known and unknown protein structures.
Rosetta@home is a volunteer computing project researching protein structure prediction on the Berkeley Open Infrastructure for Network Computing (BOINC) platform, run by the Baker lab. Rosetta@home aims to predict protein–protein docking and design new proteins with the help of about fifty-five thousand active volunteered computers processing at over 487,946 GigaFLOPS on average as of September 19, 2020. Foldit, a Rosetta@home videogame, aims to reach these goals with a crowdsourcing approach. Though much of the project is oriented toward basic research to improve the accuracy and robustness of proteomics methods, Rosetta@home also does applied research on malaria, Alzheimer's disease, and other pathologies.
Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein. Homology modeling relies on the identification of one or more known protein structures likely to resemble the structure of the query sequence, and on the production of an alignment that maps residues in the query sequence to residues in the template sequence. It has been seen that protein structures are more conserved than protein sequences amongst homologues, but sequences falling below a 20% sequence identity can have very different structure.
The global distance test (GDT), also written as GDT_TS to represent "total score", is a measure of similarity between two protein structures with known amino acid correspondences but different tertiary structures. It is most commonly used to compare the results of protein structure prediction to the experimentally determined structure as measured by X-ray crystallography, protein NMR, or, increasingly, cryoelectron microscopy. The metric was developed by Adam Zemla at Lawrence Livermore National Laboratory and originally implemented in the Local-Global Alignment (LGA) program. It is intended as a more accurate measurement than the common root-mean-square deviation (RMSD) metric - which is sensitive to outlier regions created, for example, by poor modeling of individual loop regions in a structure that is otherwise reasonably accurate. The conventional GDT_TS score is computed over the alpha carbon atoms and is reported as a percentage, ranging from 0 to 100. In general, the higher the GDT_TS score, the more closely a model approximates a given reference structure.
EVA was a continuously running benchmark project for assessing the quality and value of protein structure prediction and secondary structure prediction methods. Methods for predicting both secondary structure and tertiary structure - including homology modeling, protein threading, and contact order prediction - were compared to results from each week's newly solved protein structures deposited in the Protein Data Bank. The project aimed to determine the prediction accuracy that would be expected for non-expert users of common, publicly available prediction webservers; this is similar to the related LiveBench project and stands in contrast to the bi-yearly benchmark CASP, which aims to identify the maximum accuracy achievable by prediction experts.
LiveBench is a continuously running benchmark project for assessing the quality of protein structure prediction and secondary structure prediction methods. LiveBench focuses mainly on homology modeling and protein threading but also includes secondary structure prediction, comparing publicly available webserver output to newly deposited protein structures in the Protein Data Bank. Like the EVA project and unlike the related CASP and CAFASP experiments, LiveBench is intended to study the accuracy of predictions that would be obtained by non-expert users of publicly available prediction methods. A major advantage of LiveBench and EVA over CASP projects, which run once every two years, is their comparatively large data set.
CAFASP, or the Critical Assessment of Fully Automated Structure Prediction, is a large-scale blind experiment in protein structure prediction that studies the performance of automated structure prediction webservers in homology modeling, fold recognition, and ab initio prediction of protein tertiary structures based only on amino acid sequence. The experiment runs once every two years in parallel with CASP, which focuses on predictions that incorporate human intervention and expertise. Compared to related benchmarking techniques LiveBench and EVA, which run weekly against newly solved protein structures deposited in the Protein Data Bank, CAFASP generates much less data, but has the advantage of producing predictions that are directly comparable to those produced by human prediction experts. Recently CAFASP has been run essentially integrated into the CASP results rather than as a separate experiment.
In computational biology, de novo protein structure prediction refers to an algorithmic process by which protein tertiary structure is predicted from its amino acid primary sequence. The problem itself has occupied leading scientists for decades while still remaining unsolved. According to Science, the problem remains one of the top 125 outstanding issues in modern science. At present, some of the most successful methods have a reasonable probability of predicting the folds of small, single-domain proteins within 1.5 angstroms over the entire structure.
Foldit is an online puzzle video game about protein folding. It is part of an experimental research project developed by the University of Washington, Center for Game Science, in collaboration with the UW Department of Biochemistry. The objective of Foldit is to fold the structures of selected proteins as perfectly as possible, using tools provided in the game. The highest scoring solutions are analyzed by researchers, who determine whether or not there is a native structural configuration that can be applied to relevant proteins in the real world. Scientists can then use these solutions to target and eradicate diseases and create biological innovations. A 2010 paper in the science journal Nature credited Foldit's 57,000 players with providing useful results that matched or outperformed algorithmically computed solutions.
RAPTOR is protein threading software used for protein structure prediction. It has been replaced by RaptorX, which is much more accurate than RAPTOR.
RaptorX is a software and web server for protein structure and function prediction that is free for non-commercial use. RaptorX is among the most popular methods for protein structure prediction. Like other remote homology recognition/protein threading techniques, RaptorX is able to regularly generate reliable protein models when the widely used PSI-BLAST cannot. However, RaptorX is also significantly different from those profile-based methods in that RaptorX excels at modeling of protein sequences without a large number of sequence homologs by exploiting structure information. RaptorX Server has been designed to ensure a user-friendly interface for users inexpert in protein structure prediction methods.
Continuous Automated Model EvaluatiOn (CAMEO) is a community-wide project to continuously evaluate the accuracy and reliability of protein structure prediction servers in a fully automated manner. CAMEO is a continuous and fully automated complement to the bi-annual CASP experiment.
I-TASSER is a bioinformatics method for predicting three-dimensional structure model of protein molecules from amino acid sequences. It detects structure templates from the Protein Data Bank by a technique called fold recognition. The full-length structure models are constructed by reassembling structural fragments from threading templates using replica exchange Monte Carlo simulations. I-TASSER is one of the most successful protein structure prediction methods in the community-wide CASP experiments.
AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. The program is designed as a deep learning system.
Rita Casadio is an Adjunct Professor of Biochemistry/Biophysics in the Department of Pharmacy and Biotechnology at the University of Bologna.
IntFOLD is fully automated, integrated pipeline for prediction of 3D structure and function from amino acid sequences. The pipeline is wrapped up and deployed as a Web Server. The core of the server method is quality assessment using built-in accuracy self-estimates (ASE) which improves performance prediction of 3D model using ModFOLD.
John Michael Jumper is an American senior research scientist at DeepMind Technologies. Jumper and his colleagues created AlphaFold, an artificial intelligence (AI) model to predict protein structures from their amino acid sequence with high accuracy. Jumper has stated that the AlphaFold team plans to release 100 million protein structures. The scientific journal Nature included Jumper as one of the ten "people who mattered" in science in their annual listing of Nature's 10 in 2021.
