| Abstract: | A method has been developed for minimizing the energy of a polypeptide with rigid geometry while keeping all disulfide loops closed exactly. Exact closure of disulfide loops implies that some dihedral angles become implicit functions of the remaining dihedral angles in the polypeptide; the efficacy of the method is related to the manner in which the implicitly defined dihedral angles are chosen. The method has been used to find minimum-energy conformations of bovine pancreatic trypsin inhibitor, ribonuclease A, crambin, the defensin HNP3 dimer, and ω-conotoxin. For the first two proteins, the starting conformations for energy minimization had been derived previously from crystal structures using pseudopotentials to keep the disulfide loops almost closed. Starting conformations for the remaining three proteins were derived from their crystal or NMR structures by similar procedures. In all cases, the energy-minimized structures had a significantly and, in some cases, substantially, lower energy than the starting structures. The RMS deviations between the exactly closed energy- minimized structures and the crystal or NMR structures from which they were derived ranged from 0.9 Å to 1.9 Å, suggesting that the computed structures can serve as “regularized” native structures for these proteins. The energy of a ribonuclease derivative lacking the 65–72 disulfide bridge was minimized using the procedure; the result showed that this derivative has a low-energy structure with a conformation very close to that of native ribonuclease, and is consistent with its postulated role in the folding of ribonuclease. These results offer strong support for the validity of the rigid-geometry model in the studies of the conformational energy of proteins. © 1997 by John Wiley & Sons, Inc. |
