Faster but Not Sweeter: A Model of Escherichia coli Re-level Lipopolysaccharide for Martini 3 and a Martini 2 Version with Accelerated Kinetics.

Abstract

Lipopolysaccharide (LPS) is a complex glycolipid molecule that is the main lipidic component of the outer leaflet of the outer membrane of Gram-negative bacteria. It has very limited lateral motion compared to phospholipids, which are more ubiquitous in biological membranes, including in the inner leaflet of the outer membrane of Gram-negative bacteria. The slow-moving nature of LPS can present a hurdle for molecular dynamics simulations, given that the (pragmatically) accessible timescales to simulations are currently limited to microseconds, during which LPS displays some conformational dynamics but hardly any lateral diffusion. Thus, it is not feasible to observe phenomena such as insertion of molecules, including antibiotics/antimicrobials, directly into the outer membrane from the extracellular side nor to observe LPS dissociating from proteins via molecular dynamics using currently available models at the atomistic and more coarse-grained levels of granularity. Here, we present a model of deep rough LPS compatible with the Martini 2 coarse-grained force field with scaled down nonbonded interactions to enable faster diffusion. We show that the faster-diffusing LPS model is able to reproduce the salient biophysical properties of the standard models, but due to its faster lateral motion, molecules are able to penetrate deeper into membranes containing the faster model. We show that the fast ReLPS model is able to reproduce experimentally determined patterns of interaction with outer membrane proteins while also allowing for LPS to associate and dissociate with proteins within microsecond timescales. We also complete the Martini 3 LPS toolkit for Escherichia coli by presenting a (standard) model of deep rough LPS for this force field.