Assessing the Fast Prediction of Peptide Conformers and the Impact of Non-Natural Modifications

We present an assessment of different approaches to predict peptide structures using modeling tools. Several small molecule, protein, and peptide-focused methodologies were used for the fast prediction of conformers for peptides shorter than 30 amino acids. We assessed the effect of including restraints based on annotated or predicted secondary structure motifs. A number of peptides in bound conformations and in solution were collected to compare the tools. In addition, we studied the impact of changing single amino acids to non-natural residues using molecular dynamics simulations. Deep learning methods such as AlphaFold2, or the combination of physics-based approaches with secondary structure information, produce the most accurate results for natural sequences. In the case of peptides with non-natural modifications, modeling the peptide containing natural amino acids first and then modifying and simulating the peptide using benchmarked force fields is a recommended pipeline. The results can guide the modeling of oligopeptides for drug discovery projects.