A fast algorithm for the interactive docking maneuver with flexible macromolecules and probes

A new algorithm for the interactive docking maneuver is presented. Full attention is given to the flexibility of both substrate and macromolecule, i.e., all the fragments are allowed to move. It is assumed that any numerical quantity which depends only on the isolated macromolecule at energy minimum is disposable when approximate expressions are derived. The central idea is the concept of relevant docking coordinates which reflect the essential features of the macromolecular deformations during the docking maneuver and which substantially diminish the number of considered degrees of freedom (DF). The conformational energy is divided into two parts. The first part, represented by condensed potential functions, needs no approximations. For the second part, termed E_rest , a quadratic approximation in the subspace spanned by the relevant docking coordinates is used. All the pairwise interactions between the atoms of the macromolecule are eliminated. A simple computational example using the ECEPP force field is given. Atomic coordinate computations are simplified by the introduction of virtual rotation axes for the backbone. In connection with drug design the concept of pressure pattern is defined and related to quantities appearing in the energy gradient. Extensions to substrate induced allosteric transitions are discussed.