Modulation of free energy landscapes as a strategy for the design of antimicrobial peptides

Computational design of antimicrobial peptides (AMPs) is a promising area of research for developing novel agents against drug-resistant bacteria. AMPs are present naturally in many organisms, from bacteria to humans, a time-tested mechanism that makes them attractive as effective antibiotics. Depending on the environment, AMPs can exhibit α-helical or β-sheet conformations, a mix of both, or lack secondary structure; they can be linear or cyclic. Prediction of their structures is challenging but critical for rational design. Promising AMP leads can be developed using essentially two approaches: traditional modeling of the physicochemical mechanisms that determine peptide behavior in aqueous and membrane environments and knowledge-based, e.g., machine learning (ML) techniques, that exploit ever-growing AMP databases. Here, we explore the conformational landscapes of two recently ML-designed AMPs, characterize the dependence of these landscapes on the medium conditions, and identify features in peptide and membrane landscapes that mediate protein-membrane association. For both peptides, we observe greater conformational diversity in an aqueous solvent than in a less polar solvent, and one peptide is seen to alter its conformation more dramatically than the other upon the change of solvent. Our results support the view that structural rearrangement in response to environmental changes is central to the mechanism of membrane-structure disruption by linear peptides. We expect that the design of AMPs by ML will benefit from the incorporation of peptide conformational substates as quantified here with molecular simulations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10867-022-09605-z.