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A multi-resolution approach to cation-induced polymorphism of lipopolysaccharide aggregates


Lipopolysaccharides (LPS) are the major components of the outer membrane (OM) of Gram-negative bacteria, a highly effective permeability barrier against antibiotics and the host cell defense system. Critical physical-chemical properties of the OM (e.g. stability, low permeability, hydration) are modulated by the hydration dynamics of metals coordinating phosphate groups from distinct LPS molecules. The present proposal aims to establish the role of a series of alkali and alkaline earth metals on the stability and structural transitions of LPS aggregates via a multi-resolution computational approach. At the highest resolution, it will make use of QM/MM methodologies to determine electronic properties critical for the accurate description of cation hydration dynamics. These properties will be used to refine the classical description of cations in a previously developed force field extension for glycolipids and validated via atomistic simulations of the LPS aggregates containing a variety of mono- and divalent cations. At the lowest resolution, these MD-derived structural ensembles will serve as reference systems for the development of an accurate coarse-grain representation of LPS and cations compatible with the hybrid particle-field (hPF) method. This approach will allow to assess of the accuracy of additive potentials for use in classical MD simulations and to develop accurate hPF-compatible models that can sample time- and spatial scales inaccessible to atomistic representations. The present proposal will provide the computational scaffold for a comprehensive characterization of the microscopic mechanism underlying cation-induced structural transitions in glycolipid aggregates. It is anticipated that this research outcome will be of relevance for the development of new antimicrobials that target the cell wall of Gram-negative bacteria. This multidisciplinary project will be carried out as an extension of previously established international collaborations. (AU)

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