Assessment of the MARTINI 3 Performance for Short Peptide Self-Assembly.

The coarse-grained MARTINI force field, initially developed for membranes, has proven to be an exceptional tool for investigating supramolecular peptide assemblies. Over the years, the force field underwent refinements to enhance accuracy, enabling, for example, the reproduction of protein-ligand interactions and constant pH behavior. However, these protein-focused improvements seem to have compromised its ability to model short peptide self-assembly. In this study, we assess the performance of MARTINI 3 in reproducing peptide self-assembly using the well-established diphenylalanine (FF) as our test case. Unlike its success in version 2.1, FF does not even exhibit aggregation in version 3. By systematically exploring parameters for the aromatic side chains and charged backbone beads, we established a parameter set that effectively reproduces tube formation. Remarkably, these parameter adjustments also replicate the self-assembly of other di- and tripeptides and coassemblies. Furthermore, our analysis uncovers pivotal insights for enhancing the performance of MARTINI in modeling short peptide self-assembly. Specifically, we identify issues stemming from overestimated hydrophilicity arising from charged termini and disruptions in π-stacking interactions due to insufficient planarity in aromatic groups and a discrepancy in intermolecular distances between this and backbone-backbone interactions. This investigation demonstrates that strategic modifications can harness the advancements offered by MARTINI 3 for the realm of short peptide self-assembly.