Proteins are composed of simple and elementary secondary structures, including turns, alpha-helices and beta-sheets. An in-depth understanding of the folding of these secondary structural elements is an important step toward solving the protein-folding problem, one of the major unsolved problems in biological science. Short peptides (less than 20 residues), which adopt defined secondary structures in solution (turn, alpha-helix and beta-hairpin), are excellent model systems with which to study the folding of protein secondary structures. An effective approach to the secondary structure folding is to simulate the folding and unfolding of peptides using molecular dynamics simulation, with an all atom-based model for peptides and in the presence of explicit water. One limitation of such an approach is that the time scale of peptide folding ranges from hundreds of nanoseconds for alpha-helices to microseconds for beta-hairpins. This makes it computationally difficult to employ molecular dynamics (MD) simulations using current computing power. We have recently developed a new, unconventional MD simulation method. Using this new MD method, the folding and unfolding of peptides using an all-atom model in explicit waters can be observed over hundreds of picoseconds of simulation time. This provides an unprecedented opportunity to study the folding of protein secondary structures. Our preliminary data suggest that simulation results obtained using this new MD method are in good agreement with NMR and CD experiments. The preliminary analysis on the simulation trajectory has provided important insight to the secondary structure folding mechanism. Presently, further careful validation of this new MD method is warranted and extended simulations and analyses are needed.
The specific aims of this grant are: (1) Using the new MD method, conducting prolonged folding simulations in explicit waters of a 5-mer peptide, which adopts a type II reverse turns, a 16-mer peptide, which has a 50 percent alpha-helix content and a 9-mer peptide, which has a significant population of beta-hairpin structure in solution. (2) Validating the new MD simulation method by direct comparison the simulation results with results obtained from CD and NMR experiments, under different simulation conditions and from prolonged conventional MD simulations. (3) Elucidating the folding mechanism of protein secondary structures through statistical and microscopic analyses of simulation trajectory.
| Wu, Xiongwu; Wang, Shaomeng; Brooks, Bernard R (2002) Direct observation of the folding and unfolding of a beta-hairpin in explicit water through computer simulation. J Am Chem Soc 124:5282-3 |
