A Generalized Attraction-Repulsion Potential and Revisited Fragment Library Improves PEP-FOLD Peptide Structure Prediction.

Fast and accurate structure prediction is essential to the study of peptide function, molecular targets, and interactions and has been the subject of considerable efforts in the past decade. In this work, we present improvements to the popular simplified PEP-FOLD technique for small peptide structure prediction. PEP-FOLD originality is threefold: (i) it uses a predetermined structural alphabet, (ii) it uses a sequential algorithm to reconstruct the tridimensional structures of these peptides in a discrete space using a fragment library, and (iii) it assesses the energy of these structures using a coarse-grained representation in which all of the backbone atoms but the α-hydrogen are present, and the side chain corresponds to a unique bead. In former versions of PEP-FOLD, a van der Waals formulation was used for non-bonded interactions, with each side chain being associated with a fixed radius. Here, we explore the relevance of using instead a generalized formulation in which not only the optimal distance of interaction and the energy at this distance are parameters but also the distance at which the potential is zero. This allows each side chain to be associated with a different radius and potential energy shape, depending on its interaction partner, and in principle to make more effective the coarse-grained representation. In addition, the new PEP-FOLD version is associated with an updated library of fragments. We show that these modifications lead to important improvements for many of the problematic targets identified with the former PEP-FOLD version while maintaining already correct predictions. The improvement is in terms of both model ranking and model accuracy. We also compare the PEP-FOLD enhanced version to state-of-the-art techniques for both peptide and structure predictions: APPTest, RaptorX, and AlphaFold2. We find that the new predictions are superior, in particular with respect to the prediction of small β-targets, to those of APPTest and RaptorX and bring, with its original approach, additional understanding on folded structures, even when less precise than AlphaFold2. With their strong physical influence, the revised structural library and coarse-grained potential offer, however, the means for a deeper understanding of the nature of folding and open a solid basis for studying flexibility and other dynamical properties not accessible to IA structure prediction approaches.