Testing recently-developed molecular dynamics protocols for structure prediction of polypeptides and prion proteins.

Abstract

Two MD protocols were recently developed that allow a polypeptide to search the PE surface in search of the global PE minimum, which should correspond to the experimental structure. alpha-helical secondary structures have previously been tested. We tested an additional alpha helix (C-peptide of ribonuclease A), and we extended the tests with two beta-hairpin secondary structures (tryptophan zipper 2 and the B1 domain(41--56) of protein G). For the C-peptide of ribonuclease A, the a helix was the dominate secondary structure, but a beta hairpin was found, which to our knowledge had not previously been reported. For the tryptophan zipper 2 and the B1 domain(41--56) of protein G, the beta hairpin was reproduced but alternative conformations were also found. After these test cases, we simulated a small protein (betabetaalpha5) that contained both secondary structural motifs and an overall tertiary structure. The secondary structures were reproduced, but the tertiary structure was not maintained. Finally, we attempted to predict possible conformations for a 64-residue protein, Ure2p, which is implicated in amyloid diseases of yeast. We found that Ure2p(1--64) was dominated by helical conformations. The DIVE and DIP protocols will need to be tested further with different polypeptides and proteins and using more recent force fields. Ure2p(1--64) should be simulated from additional secondary structures such as a beta sheet or a combination of alpha helices and beta hairpins.