Computer manipulation of (macro)molecules with the method of local change

In computer manipulation of macromolecules bond lengths and bond angles as well as some dihedral angles frequently are held fixed at ideal values observed in small model compounds. Changes of the conformation are then made by internal rotation about chemical bonds. The result of each rotation is the relative motion of large parts of the molecule; this will therefore be referred to as the global method of changing the conformation. The effect of this method is similar to manipulation of a stick model of the molecule. A method is described for manipulating the conformation in which only one atom is moved at a time; hence the name, local method. Each movement is made in order to improve the immediate environment of the atom by decreasing the differences between bond lengths, bond angles and fixed dihedral angles near this atom and their ideal values. Small displacements are calculated and applied for each atom in turn, and this is repeated a number of times for the entire molecule. At the same time, one may require that the position of each atom is not moved too far away from the starting position, so as to give idealization of the starting conformation or model building. Alternatively, inclusion of a term tending to lower the contributions to the intramolecular energy (van der Waals attractive energy, repulsive energy, electrostatic energy) gives energy minimization. A description is given of the progress of the model-building calculation with a fifteen-residue segment of the protein rubredoxin as a test case. The resulting conformation is found to be very close to the best global fit obtainable. This best global fit is obtained by constructing a global fit to the locally fit model and further adjusting this intermediate conformation to improve the agreement with the starting coordinates. A global fit constructed to the original data is found to be inferior. It corresponds to a higher relative minimum of the sum of the squares of the distances between the model coordinates and those to be fitted; the conformation of two side chains is qualitatively different in the two global fits. An example shows how the method is suitable for building trial conformations of chain segments. Finally, advantages of the local method are pointed out which, it is believed, make its use preferable for model building in an interactive computing environment.