TARGETED MOLECULAR-DYNAMICS SIMULATION OF CONFORMATIONAL CHANGE - APPLICATION TO THE T[--]R TRANSITION IN INSULIN

A novel method to calculate transition pathways between two known protein conformations is presented. It is based on a molecular dynamics simulation starting from one conformational state as initial structure and using the other for a directing constraint. The method is exemplified with the T <-- --> R transition of insulin. The most striking difference between these conformational states is that in T the 8 N-terminal residues of the B chain are arranged as an extended strand whereas in R they are forming a helix. Both the transition from T to R and from R to T were simulated. The method proves capable of finding a continuous pathway for each direction which are moderately different. The refolding processes are illustrated by a series of transient structures and pairs of PHI, PSI angles selected from the time course of the simutations. In the T --> R direction the helix is formed in the tast third of the transition, while in the R --> T direction it is preserved during more than half of the simutation period. The results are discussed in comparison with those of an atternative method recently apptied to the T --> R transition of insulin which is based on targeted energy minimisation.