De novo structure prediction
ab initio Structure Prediction
Summary ...
Contents
Further reading and resources
| Ambrish, R. & Zhang, Y. (2012) Protein Structure Prediction. Encyclopedia of Life Sciences |
| (pmid: None) The goal of protein structure prediction is to estimate the spatial position of every atom of protein molecules from the amino acid sequence by computational methods. Depending on the availability of homologous templates in the PDB library, structure prediction approaches are categorised into template-based modelling (TBM) and free modelling (FM). While TBM is by far the only reliable method for high-resolution structure prediction, challenges in the field include constructing the correct folds without using template structures and refining the template models closer to the native state when templates are available. Nevertheless, the usefulness of various levels of protein structure predictions have been convincingly demonstrated in biological and medical applications. |
| Morcos et al. (2011) Direct-coupling analysis of residue coevolution captures native contacts across many protein families. Proc Natl Acad Sci U.S.A 108:E1293-301. (pmid: 22106262) |
|
[ PubMed ] [ DOI ] The similarity in the three-dimensional structures of homologous proteins imposes strong constraints on their sequence variability. It has long been suggested that the resulting correlations among amino acid compositions at different sequence positions can be exploited to infer spatial contacts within the tertiary protein structure. Crucial to this inference is the ability to disentangle direct and indirect correlations, as accomplished by the recently introduced direct-coupling analysis (DCA). Here we develop a computationally efficient implementation of DCA, which allows us to evaluate the accuracy of contact prediction by DCA for a large number of protein domains, based purely on sequence information. DCA is shown to yield a large number of correctly predicted contacts, recapitulating the global structure of the contact map for the majority of the protein domains examined. Furthermore, our analysis captures clear signals beyond intradomain residue contacts, arising, e.g., from alternative protein conformations, ligand-mediated residue couplings, and interdomain interactions in protein oligomers. Our findings suggest that contacts predicted by DCA can be used as a reliable guide to facilitate computational predictions of alternative protein conformations, protein complex formation, and even the de novo prediction of protein domain structures, contingent on the existence of a large number of homologous sequences which are being rapidly made available due to advances in genome sequencing. |
| Marks et al. (2011) Protein 3D structure computed from evolutionary sequence variation. PLoS ONE 6:e28766. (pmid: 22163331) |
|
[ PubMed ] [ DOI ] The evolutionary trajectory of a protein through sequence space is constrained by its function. Collections of sequence homologs record the outcomes of millions of evolutionary experiments in which the protein evolves according to these constraints. Deciphering the evolutionary record held in these sequences and exploiting it for predictive and engineering purposes presents a formidable challenge. The potential benefit of solving this challenge is amplified by the advent of inexpensive high-throughput genomic sequencing.In this paper we ask whether we can infer evolutionary constraints from a set of sequence homologs of a protein. The challenge is to distinguish true co-evolution couplings from the noisy set of observed correlations. We address this challenge using a maximum entropy model of the protein sequence, constrained by the statistics of the multiple sequence alignment, to infer residue pair couplings. Surprisingly, we find that the strength of these inferred couplings is an excellent predictor of residue-residue proximity in folded structures. Indeed, the top-scoring residue couplings are sufficiently accurate and well-distributed to define the 3D protein fold with remarkable accuracy.We quantify this observation by computing, from sequence alone, all-atom 3D structures of fifteen test proteins from different fold classes, ranging in size from 50 to 260 residues, including a G-protein coupled receptor. These blinded inferences are de novo, i.e., they do not use homology modeling or sequence-similar fragments from known structures. The co-evolution signals provide sufficient information to determine accurate 3D protein structure to 2.7-4.8 Å C(α)-RMSD error relative to the observed structure, over at least two-thirds of the protein (method called EVfold, details at http://EVfold.org). This discovery provides insight into essential interactions constraining protein evolution and will facilitate a comprehensive survey of the universe of protein structures, new strategies in protein and drug design, and the identification of functional genetic variants in normal and disease genomes. |
| Hopf et al. (2012) Three-dimensional structures of membrane proteins from genomic sequencing. Cell 149:1607-21. (pmid: 22579045) |
|
[ PubMed ] [ DOI ] We show that amino acid covariation in proteins, extracted from the evolutionary sequence record, can be used to fold transmembrane proteins. We use this technique to predict previously unknown 3D structures for 11 transmembrane proteins (with up to 14 helices) from their sequences alone. The prediction method (EVfold_membrane) applies a maximum entropy approach to infer evolutionary covariation in pairs of sequence positions within a protein family and then generates all-atom models with the derived pairwise distance constraints. We benchmark the approach with blinded de novo computation of known transmembrane protein structures from 23 families, demonstrating unprecedented accuracy of the method for large transmembrane proteins. We show how the method can predict oligomerization, functional sites, and conformational changes in transmembrane proteins. With the rapid rise in large-scale sequencing, more accurate and more comprehensive information on evolutionary constraints can be decoded from genetic variation, greatly expanding the repertoire of transmembrane proteins amenable to modeling by this method. |
| Marks et al. (2012) Protein structure prediction from sequence variation. Nat Biotechnol 30:1072-80. (pmid: 23138306) |
|
[ PubMed ] [ DOI ] Genomic sequences contain rich evolutionary information about functional constraints on macromolecules such as proteins. This information can be efficiently mined to detect evolutionary couplings between residues in proteins and address the long-standing challenge to compute protein three-dimensional structures from amino acid sequences. Substantial progress has recently been made on this problem owing to the explosive growth in available sequences and the application of global statistical methods. In addition to three-dimensional structure, the improved understanding of covariation may help identify functional residues involved in ligand binding, protein-complex formation and conformational changes. We expect computation of covariation patterns to complement experimental structural biology in elucidating the full spectrum of protein structures, their functional interactions and evolutionary dynamics. |
