Protein folding by restrained energy minimization and molecular dynamics.

Native-like folded conformations of bovine pancreatic trypsin inhibitor protein are calculated by searching for conformations with the lowest possible potential energy. Twenty-five random starting structures are subjected to soft-atom restrained energy minimization with respect to both the torsion angles and the atomic Cartesian co-ordinates. The restraints used to limit the search include the three disulphide bridges and the 16 main-chain hydrogen bonds that define the native secondary structure. The potential energy functions used are detailed and include terms that allow bond stretching, bond angle bending, bond twisting, van der Waals' forces and hydrogen bonds. Novel features of the methods used include soft-atoms to make restrained energy minimization work, writhing numbers to classify chain threadings, and molecular dynamics followed by energy minimization to anneal the conformations and reduce their energies further. Conformations are analysed using writhing numbers, torsion angle distributions, hydrogen bonds and accessible surface areas. The resulting conformations are very diverse in their chain threadings, energies and root-mean-square deviations from the X-ray structure. There is a relationship between the root-mean-square deviation and the energy, in that the lowest energy conformations are also closest to the X-ray structure. The best conformation calculated here has a root-mean-square deviation of only 3 A and shows the same special threading found in the X-ray structure. The methods introduced here have wide ranging applications; they can be used to build models of protein conformations that have low energy values and obey a wide variety of restraints.