Assembly of a tetrameric alpha-helical bundle: Computer simulations on an intermediate-resolution protein model

Discontinuous molecular dynamics (DMD) simulation on an intermediate-resolu tion protein model is used to study the folding of an isolated, small model peptide to an amphipathic alpha -helix and the assembly of four of these m odel peptides into a four-helix bundle. A total of 129 simulations were per formed on the isolated peptide, and 50 simulations were performed on the fo ur-peptide system. Simulations efficiently sample conformational space allo wing complete folding trajectories from random initial configurations to be observed within 15 min for the one-peptide system and within 15 h for the four-peptide system on a 500-MHz workstation. The native structures of both the alpha -helix and the four-helix bundle are consistent with experimenta l characterization studies and with results from previous simulations on th ese model peptides. In both the one- and four-peptide systems, the native s tate is achieved during simulations within an optimal temperature range, a phenomenon also observed experimentally. The ease with which our simulation s yield reasonable estimates of folded structures demonstrates the power of the intermediate-resolution model developed for this work and the DMD algo rithm and suggests that simulations of very long times and of multiprotein systems may be possible with this model. (C) 2001 Wiley-Liss, Inc.