Simulation of protein folding by reaction path annealing

We present a systematic application of reaction path sampling to computer s imulations of the folding of peptides and small proteins at atomic resoluti on in the presence of solvent. We use a simulated annealing protocol to gen erate an ensemble of room temperature folding trajectories of fixed length, which connect predetermined initial and final states. The trajectories are distributed according to a discretized version of the Onsager-Machlup acti on functional. We show that, despite the enormous practical restrictions pl aced on the number of time slices which can be explored, some of the basic kinetic features found experimentally for the folding of peptides and small proteins are exhibited in the nature of the reaction paths sampled. We tes t the method on three systems: A 12 residue alpha -helical peptide, a 16 re sidue beta -hairpin peptide, and the 36 residue avian Pancreatic Polypeptid e (aPP). All systems are represented at atomic resolution, and include expl icit water molecules. For the 12 residue alpha -helix, we find that (i,i 3) hydrogen bonds can play a significant role in the folding pathway, with specific (i,i + 3) bonds appearing, then transforming to the corresponding (i,i + 4) hydrogen bond for some, but not all of the native hydrogen bonds. For the beta -hairpin and aPP, hydrophobic interactions play a dominant ro le, with nonbonded interactions consistently appearing before hydrogen bond s. This is true both at the level of tertiary structure, and at the level o f individual hydrogen bonds which tend to form only after stabilizing nonbo nded interactions have already formed between the residues involved. (C) 20 01 American Institute of Physics.