We present the newest version of the GROningen MOlecular Simulation program package, GROMOS96. GROMOS96 has been developed for the dynamic modelling of (bio)molecules using the methods of molecular dynamics, stochastic dynamics, and energy minimization as well as the path-integral formalism. An overview of its functionality is given, highlighting methodology not present in the last major release, GROMOS87. The organization of the code is outlined, and reliability, testing, and efficiency issues involved in the design of this large (73 000 lines of FORTRAN77 code) and complex package are discussed. Finally, we present two applications illustrating new functionality: local elevation simulation and molecular dynamics in four spatial dimensions.

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 a, t angles selected from the time course of the nimutations. 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.

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