PACE Force Field for Protein Simulations. 2. Folding Simulations of Peptides

We present the application of our recently developed PACE force field to the folding of peptides. These peptides include α-helical (AK17 and Fs), β-sheet (GB1m2 and Trpzip2), and mixed helical/coil (Trp-cage) peptides. With replica exchange molecular dynamics (REMD), our force field can fold the five peptides into their native structures while maintaining their stabilities reasonably well. Our force field is also able to capture important thermodynamic features of the five peptides that have been observed in previous experimental and computational studies, such as different preferences for a helix−turn−helix topology for AK17 and Fs, the relative contribution of four hydrophobic side chains of GB1p to the stability of β-hairpin, and the distinct role of a hydrogen bond involving Trp-H_ε and a D9/R16 salt bridge in stabilizing the Trp-cage native structure. Furthermore, multiple folding and unfolding events are observed in our microsecond-long normal MD simulations of AK17, Trpzip2, and Trp-cage. These simulations provide mechanistic information such as a “zip-out” pathway of the folding mechanism of Trpzip2 and the folding times of AK17 and Trp-cage, which are estimated to be about 51 ± 43 ns and 270 ± 110 ns, respectively. A 600 ns simulation of the peptides can be completed within one day. These features of our force field are potentially applicable to the study of thermodynamics and kinetics of real protein systems.