Helix propensities of short peptides: Molecular dynamics versus bioinformatics

Knowledge‐based potential functions for protein structure prediction assume that the frequency of occurrence of a given structure or a contact in the protein database is a measure of its free energy. Here, we put this assumption to test by comparing the results obtained from sequence‐structure cluster analysis with those obtained from long all‐atom molecular dynamics simulations. Sixty‐four eight‐residue peptide sequences with varying degrees of similarity to the canonical sequence pattern for amphipathic helix were drawn from known protein structures, regardless of whether they were helical in the protein. Each was simulated using AMBER6.0 for at least 10 ns using explicit waters. The total simulation time was 1176 ns. The resulting trajectories were tested for reproducibility, and the helical content was measured. Natural peptides whose sequences matched the amphipathic helix motif with greater than 50% confidence were significantly more likely to form helix during the course of the simulation than peptides with lower confidence scores. The sequence pattern derived from the simulation data closely resembles the motif pattern derived from the database cluster analysis. The difficulties encountered in sampling conformational space and sequence space simultaneously are discussed. Key words: Proteins 2003;50:552–562. © 2003 Wiley‐Liss, Inc.