Protein avian pancreatic polypeptide

A hybrid approach of the extended scaled particle theory (SPT) and the Poisson-Boltzmann (PB) equation for the solvation free energy of non-polar and polar solutes has been proposed by us. This new method is applied for the hydration free energy of the protein, avian pancreatic polypeptide (36 residues). The contributions form the cavity formation and the attractive interaction between the solute and the solvent to the solvation free energy compensate each other. The electrostatic conffibution is much larger than other terms in this hyelration free energy, because hydrophilic residues are ionized in water. This work is the first step toward further applications of our new method to free energy difference calculation appeared in the stability analysis of protein. 

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. 

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...

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. 

Zhang H, Wong CF, Thacher T, Rabitz H. 1995. Parametric sensitivity analysis of avian pancreatic polypeptide (APP). Proteins Struct. Fund. Genet. 23 218... 

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. 

Simulations of BPTI (bovine pancreatic trypsin inhibitor) in van der Waals solvents have been reported [74, 75], the density and molecular size were chosen to simulate those of water. More realistic water representations were used in further simulations [18, 76, 77]. Avian pancreatic polypeptide hormone in crystal and in aqueous solution has been reported by Kruger [78]. These studies tend to indicate that the calculations in vacuo represent fairly correctly the motion of the protein core, while exposed sidechains react more strongly to solvent effects. 

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