Avian pancreatic polypeptide, molecular

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. 

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. 

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. 

---