Protein structure known

Figure 5.10 Idealized diagrams of the Greek key motif. This motif is formed when one of the connections of four antiparallel fi strands is not a hairpin connection. The motif occurs when strand number n is connected to strand + 3 (a) or - 3 (b) instead of -r 1 or - 1 in an eight-stranded antiparallel P sheet or barrel. The two different possible connections give two different hands of the Greek key motif. In all protein structures known so far only the hand shown in (a) has been observed.

As already discussed in Chapter 11, there are more than 10 000 protein structures known but only about 30 3D structure types. This might be traced to a limited number of possible stable polypeptide structures but most probably reflects the evolutionary history of the diversity of proteins. There are structural motifs which repeat themselves in a multitude of enzymes which are otherwise neither structurally nor functionally related, such as TIM barrel proteins, four-helix bundle proteins, Rossmann folds, or a/j3-folds of hydrolases (Figure 16.1). 

Figure 2 lists some examples of recurrent linear sequences with standard amino acid interchanges and short-range rearrangements taken from the structures of two proteins. The occurrence of such regularities in all protein structures known so far has been pointed out by one of the authors... 

Describe the secondary protein structure known as the pleated sheet. Give two examples of materials containing proteins with this structure. 

Some medicines contain molecules based on proteins ( biopharmaceuticals ). The first and best-known example was recombinant human insulin. The environmental relevance of biopharmaceuticals is not yet clear and until now they have not been the focus of environmental research and risk management. However, structurally related compounds such as plasmids have been found in the environment. Furthermore, it is known that the protein structures known as prions are very stable. Most biopharmaceuticals are modified and/or small molecules are attached to them. Therefore, it can be expected that they will behave differently to the pure unmodified proteins. Little is known on their environmental fate and effects. 

To find appropriate empirical pair potentials from the known protein structures in the Brookhaven Protein Data Bank, it is necessary to calculate densities for the distance distribution of Ga-atoms at given bond distance d and given residue assignments ai,a2- Up to a constant factor that is immaterial for subsequent structure determination by global optimization, the potentials then ciiiergo as the negative logarithm of the densities. Since... 

As more protein structures became available it was observed that some contained more that one distinct region, with each region often having a separate function. Each of these region is usually known as a domain, a domain being defined as a polypeptide chain that can folc independently into a stable three-dimensional structure. 

Ihe rule-based approach to protein structure prediction is obviously very reliant on th quality of the initial secondary structure prediction, which may not be particularly accurate The method tends to work best if it is known to which structural class the protein belongs this can sometimes be deduced from experimental techniques such as circular dichroism... 

Koppensteiner W A, P Lackner, M Wiederstein and M J Sippl 2000. Characterization of Novel Proteins Based on Known Protein Structures. Journal of Molecular Biology 296 1139-1152. 

The amount of computation necessary to try many conformers can be greatly reduced if a portion of the structure is known. One way to determine a portion of the structure experimentally is to obtain some of the internuclear distances from two-dimensional NMR experiments, as predicted by the nuclear Over-hauser effect (NOE). Once a set of distances are determined, they can be used as constraints within a conformation search. This has been particularly effective for predicting protein structure since it is very difficult to obtain crystallographic structures of proteins. It is also possible to define distance constraints based on the average bond lengths and angles, if we assume these are fairly rigid while all conformations are accessible. 

Molecular dynamics simulations of proteins often begin with a known structure (such as an X-ray diffraction structure) that you want to maintain during equilibration. Since the solvent may contain high energy hot spots, equilibration of the protein and solvent at the same time can change the protein conformation. To avoid this, select only the water molecules and run a molecular dynamics equilibration. This relaxes the water while fixing the protein structure. Then deselect the water and equilibrate the whole system. 

At this time, approximately one-half of all sequences are delectably related to at least one protein of known structure [8-11]. Because the number of known protein sequences is approximately 500,000 [12], comparative modeling could in principle be applied to over 200,000 proteins. This is an order of magnitude more proteins than the number of experimentally determined protein structures (—13,000) [13]. Furthermore, the usefulness of comparative modeling is steadily increasing, because the number of different structural folds that proteins adopt is limited [14,15] and because the number of experimentally determined structures is increasing exponentially [16]. It is predicted that in less than 10 years at least one example of most structural folds will be known, making comparative modeling applicable to most protein sequences [6]. 

All current comparative modeling methods consist of four sequential steps (Fig. 2) [5,6]. The first step is to identify the proteins with known 3D structures that are related to the target sequence. The second step is to align them with the target sequence and pick those known structures that will be used as templates. The third step is to build the model... 

A. Identifying Known Protein Structures Related to the Target Sequence... 

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