Abstract
Although peptides have many biological and biomedical implications, an accurate method predicting their equilibrium structural ensembles from amino acid sequences and suitable for large‐scale experiments is still missing. We introduce a new approach—PEP‐FOLD—to the de novo prediction of peptides and miniproteins. It first predicts, in the terms of a Hidden Markov Model‐derived structural alphabet, a limited number of local conformations at each position of the structure. It then performs their assembly using a greedy procedure driven by a coarse‐grained energy score. On a benchmark of 52 peptides with 9–23 amino acids, PEP‐FOLD generates lowest‐energy conformations within 2.8 and 2.3 Å Cα root‐mean‐square deviation from the full nuclear magnetic resonance structures (NMR) and the NMR rigid cores, respectively, outperforming previous approaches. For 13 miniproteins with 27–49 amino acids, PEP‐FOLD reaches an accuracy of 3.6 and 4.6 Å Cα root‐mean‐square deviation for the most‐native and lowest‐energy conformations, using the nonflexible regions identified by NMR. PEP‐FOLD simulations are fast—a few minutes only—opening therefore, the door to in silico large‐scale rational design of new bioactive peptides and miniproteins. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010