Improved PEP-FOLD Approach for Peptide and Miniprotein Structure Prediction

Peptides and mini proteins have many biological and biomedical implications, which motivates the development of accurate methods, suitable for large-scale experiments, to predict their experimental or native conformations solely from sequences. In this study, we report PEP-FOLD2, an improved coarse grained approach for peptide de novo structure prediction and compare it with PEP-FOLD1 and the state-of-the-art Rosetta program. Using a benchmark of 56 structurally diverse peptides with 25–52 amino acids and a total of 600 simulations for each system, PEP-FOLD2 generates higher quality models than PEP-FOLD1, and PEP-FOLD2 and Rosetta generate near-native or native models for 95% and 88% of the targets, respectively. In the situation where we do not have any experimental structures at hand, PEP-FOLD2 and Rosetta return a near-native or native conformation among the top five best scored models for 80% and 75% of the targets, respectively. While the PEP-FOLD2 prediction rate is better than the ROSETTA prediction rate by 5%, this improvement is non-negligible because PEP-FOLD2 explores a larger conformational space than ROSETTA and consists of a single coarse-grained phase. Our results indicate that if the coarse-grained PEP-FOLD2 method is approaching maturity, we are not at the end of the game of mini-protein structure prediction, but this opens new perspectives for large-scale in silico experiments.