From Conformation to Function: Decoding the Mechanisms of Antimicrobial Peptides

• Applicant: Dr.-Ing. Monika Michaelis
• Subject Area: Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry ; Theoretical Chemistry: Molecules, Materials, Surfaces
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574903969

Antimicrobial resistance (AMR) is a major global health challenge that limits the effectiveness of conventional antibiotics and imposes a growing economic burden on healthcare systems. The clinical development pipeline for new antibiotics remains stagnant, particularly for WHO-priority and ESKAPE pathogens. Antimicrobial peptides (AMPs) represent a promising class of therapeutic candidates, as they exploit collateral sensitivity in resistant strains and typically act through membrane-disruptive mechanisms. However, the molecular principles underlying AMP function remain poorly understood, which hinders rational development and optimization. This project addresses these limitations through a convergence of enhanced sampling, multiscale simulation, spectroscopic prediction, and data-driven analysis. It aims to establish a mechanistically grounded framework for AMP structure-activity relationships, linking atomic-level dynamics to membrane interaction mechanisms and enabling predictive, simulation-based peptide design. The objectives are: • To elucidate how AMP conformational ensembles adapt upon interaction with bacterial membranes, with a focus on amphipathic transitions and environment-driven conformational selection mechanisms that underpin their activity. • To identify spectroscopic fingerprints associated with functionally relevant peptide states, enabling a direct connection between molecular structure, environment, and experimental observables. • To enable the systematic transfer of atomistic insights to coarse-grained representations, yielding a validated and scalable simulation framework for efficient peptide screening and design. • To decode the principles by which peptides perturb bacterial membranes, via binding, insertion, aggregation, and pore formation, clarifying how structural dynamics translate into membrane disruption and antimicrobial function. Innovative strategies for coarse-grained model development, such as descriptor-guided simplification and reverse-fitting based on spectroscopic signatures, will ensure that key structural features and functional mechanisms of AMPs are retained in reduced-resolution simulations. The resulting workflow bridges high-resolution simulations and scalable models and enables the identification of transferable descriptors that capture key functional features. The science to be conducted contributes to the development of computational strategies to rationally design antimicrobial peptides with enhanced efficacy and resilience to resistance.

• DFG Programme: WBP Fellowship
• International Connection: Italy
• Host: Professor Dr. Giovanni Maria Pavan