Avian pancreatic polypeptide structure

Example Crippen and Snow reported their success in developing a simplified potential for protein folding. In their model, single points represent amino acids. For the avian pancreatic polypeptide, the native structure is not at a potential minimum. However, a global search found that the most stable potential minimum had only a 1.8 Angstrom root-mean-square deviation from the native structure. 

Figure 30-5 Structure of the avian pancreatic polypeptide, a small globular protein. From Blundell et al.107...

Figure 40 Stereo view illustrating superposition of computed structure of avian pancreatic polypeptide (open circles)247 on the X-ray structure (solid circles).250 251 Only the Ca atoms are shown.

In a controversial study, Sun [34] was able to use a GA to achieve surprisingly good predictions for very small proteins, like melittin, with 26 residues, and for avian pancreatic polypeptide inhibitor, with 36 residues. The algorithm involved a very complicated scheme and was able to achieve accuracy of less than 2 A versus the native conformation. However, careful analysis of this report suggests that the algorithm took advantage of the fact that the predicted proteins were actually included, in an indirect way, in the training phase that was used to parameterize the fitness function, and in a sense the GA procedure retrieved the known structure rather than predicted it. 

Fig. 2.80. A secondary structure of avian pancreatic polypeptide. (Reprinted from M. Irisa, T. Takahashi,...

There are certain practical aspects that need to be taken into account in assessing the significance of temperature factors. Errors in measurement of intensities, arising for example from incomplete correction of radiation damage or absorption, will have more serious effects on temperature factors than on atomic positions. The data must extend to a resolution of better than 2 A, otherwise temperature factors tend to be underestimated. Restraints in the refinement which assume that positional disorders of bonded atoms are highly correlated may bias the results. However, it is encouraging that in several structures (e.g., rubredoxin [193] and avian pancreatic polypeptide [194]) where the restraints were relaxed these assumptions were found to be valid. 

NPY is a member of the pancreatic polypeptide (PP) family of peptide hormones (Glover et al., 1985 Schwartz et al., 1990). A high-resolution X-ray analysis of one member of this family, avian pancreatic polypeptide (aPP), has been reported (Blundell et al., 1981 Glover et al., 1983), and a tertiary structure, referred to as the PP-fold (or the hair-pin loop), for the PP family was proposed. The PP-fold consists of... 

Plate 13 Computer-derived model of neuropeptide Y (NPY) based on the crystal structure of avian pancreatic polypeptide (aPP). For the detailed procedure used in generating this model, see Leban et al. (1995). 

Fig. 7.3. The PP fold protein structure found in avian pancreatic polypeptide (APP) and related peptides.

The protein model on which the method is tested uses a three-atom per residue backbone and a one-atom side chain. " Optimization was carried out on melittin (26 residues), avian pancreatic polypeptide inhibitor (APPI) (36 residues), and apamin (18 residues). The fitness function used a molecular mechanics penalty as well as a penalty on the radius of gyration, which is a relatively straightforward value to obtain experimentally. In all three proteins, the GA found conformations of lower energy than that of the native structure, which was a problem with the force field, rather than with the optimization method. A standard SA method was also applied to this problem. It still found low-energy conformations, but took 100-200 times more function evaluations. 

An example employing a more realistic force field can also be found in the application of sensitivity analysis to study the determinants of the structural and thermodynamical properties of the protein avian pancreatic polypeptide (APP). It was found that the size and shape of the protein was determined to a large extent by electrostatic interactions, whereas the free energy of the protein was more sensitive to the surface-area-dependent solvation energy terms that modeled hydrophobic effects. Consequently, it is possible to develop an ad hoc force field that is designed to describe certain classes of (bio)molecular properties properly. The failure of such an ad hoc force field to describe properties of other types does not necessarily indicate that this force field is useless, rather, caution should be exercised in any attempt to apply it to other properties. 

Avian (aPP), porcine (pPP), bovine (bPP), ovine (oPP), and human (hPP) pancreatic polypeptides have been sequenced (Kimmel et a/., 1975 Floyd et a/., 1977), and the avian hormone has been crystallized (Wood et a/., 1977). X-ray analysis of monoclinic crystals of aPP (Pitts et aL, 1979) initially provided a molecular structure to 3.0 A resolution this has now been extended to 1.4 A resolution (Blundell et a/., 1980 Tickle, 1980). The asymmetric unit comprises one molecule related about a crystallographic twofold axis to an equivalent molecule with which it forms a dimer. The dimers are linked in the crystals through coordination to zinc ions. 

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