TARGETED MOLECULAR-DYNAMICS - A NEW APPROACH FOR SEARCHING PATHWAYS OF CONFORMATIONAL TRANSITIONS

Molecular dynamics simulations have proven to be a valuable tool to in vestigate the dynamic behavior of stable macromolecules at finite temp erntures. However, considerable conformational transitions take place during a simulation only accidentally or at exceptionally high tempera tures far from the range of experimental conditions. Targeted molecula r dynamics (TMD) is a method to induce a conformational change to a kn own target structure at ordinary temperature by applying a time-depend ent, purely geometrical constraint. The transition is enforced indepen dently of the height of energy barriers, while the dynamics of the mol ecule is only minimally influenced by the constraint. Simulations of d ecaalanine and insulin show the ability of the method to explore the c onfigurational space for path ways accessible at a given temperature. The transitions studied at insulin comprise unfolding of an alpha-heli cal portion and, in the reverse direction, refolding from an extended conformation. A possible application of TMD is the search for energy b arriers and stable intermediates from rather local changes up to prote in denaturation.