Protein Tertiary Structures: Prediction from Amino Acid Sequences

Abstract

Proteins have a crucial role in all cellular processes. The function of a protein is intrinsically linked to its structure, so solving protein tertiary structures is the key to understanding the biological functions of proteins. Resolving protein three‐dimensional (3D) structures is complicated and time‐consuming, so despite recent efforts to determine representative structures for each protein family, the number of known protein structures is dwarfed by the number of known protein sequences. Computational methods for the prediction of protein tertiary structures directly from their amino acid sequences have been developed to bridge this gap. These structure prediction algorithms are based on the observation that there are a limited number of protein folds and that most protein sequences will fold into one of these limited globular structures. The field of structure prediction is now quite mature and many stable methods exist for generating alignments between sequences and structures and for building 3D models.

Key Concepts:

  • Structure can be predicted from sequence because protein folds are relatively stable.

  • A wide variety of methods exist for the prediction of 3D structure from protein sequence.

  • The easiest targets are those for which it is possible to detect an evolutionary related template structure that aligns with more than 30% sequence and few gaps.

  • In these cases, structure prediction is trivial and the emphasis should be placed on all atom refinement measures.

  • Where template structures are more remotely related, maximum effort should be put into obtaining an alignment between template and target sequences.

  • Structural domains, disorder, secondary structure and important functional residues need to be considered when building a model of a target protein.

Keywords: protein structure prediction; protein folding; homology modelling; fold recognition; ab initio prediction

Figure 1.

The crystal structure of a putative nitroreductase from Mycobacterium smegmatis (PDB code: 2ymv) showing beta‐strands in red and alpha helices in teal.

Figure 2.

View of an alignment between target sequence and structural template (PDB code: 3tac) from the HHPred web server. HHPred is a particularly useful server for alignment editing. In the figure, predicted helix‐forming residues for the target (first line) and template (last line), as well as the real secondary structure for the template (penultimate line), are indicated in red with an ‘H’. There are five single residue gaps in the alignment and three (marked by a red arrow) broken helices in the template. Here, the predictor should consider shifting the gaps so that they fall in an adjacent loop region (marked as ‘C’ in the secondary structure notation). However, where possible the predictor should try not to disturb the conserved loop regions (indicated by the symbols ‘|’ and ‘+’ in the fourth line).

Figure 3.

The crystal structure of domain 1 of a hypothetical protein from Bacteroides eggerthii (in red, PDB code: 4FTD) superimposed on one of the best predictions from CASP10 (light blue, from HHPred). The nearest template had just 17% identity with the target. While the positioning of many of the secondary structure elements in the model are target structures, there are large differences in the loop regions, especially clear in the loops on the left. The positions of the side chains in the two structures (not shown) are not at all similar. The crystal structure of a putative lipoprotein from Parabacteroides distasonis (in red, PDB code: 4FVS) superimposed on a good model (light blue, from HHPred). Here, the nearest template was 43% identical to the target. With the better alignments all the helices, strands and conserved loops in the model and target structures superimpose well, and the largest differences between target and model are in nonconserved loop regions. The positions of the side chains in the first panel (not shown) where the target and template structures had just 17% identity are not at all similar. In the second panel where the target and template had 43% identity the side chains (not shown) are more or less correctly positioned in the model, with the exception of the variable loops.

Figure 4.

The crystal structure of a guide‐strand‐containing Argonaute protein silencing complex (PDB code: 3 dlb). The protein has five separate structural domains, each shown in a different colour.

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Tress, Michael(Oct 2013) Protein Tertiary Structures: Prediction from Amino Acid Sequences. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003040.pub2]