Coarse-grained molecular dynamics provides insight into the interactions of lipids and cholesterol with rhodopsin.

Protein function is a complicated interplay between structure and dynamics, which can be heavily influenced by environmental factors and conditions. This is particularly true in the case of membrane proteins, such as the visual receptor rhodopsin. It has been well documented that lipid headgroups, polyunsaturated tails, and the concentration of cholesterol in membranes all play a role in the function of rhodopsin. Recently, we used all-atom simulations to demonstrate that different lipid species have preferential interactions and possible binding sites on rhodopsin's surface, consistent with experiment. However, the limited timescales of the simulations meant that the statistical uncertainty of these results was substantial. Accordingly, we present here 32 independent 1.6 µs coarse-grained simulations exploring lipids and cholesterols surrounding rhodopsin and opsin, in lipid bilayers mimicking those found naturally. Our results agree with those found experimentally and in previous simulations, but with far better statistical certainty. The results demonstrate the value of combining all-atom and coarse-grained models with experiment to provide a well-rounded view of lipid-protein interactions.

Interactions between fengycin and model bilayers quantified by coarse-grained molecular dynamics.

Bacteria, particularly of the genus Bacillus, produce a wide variety of antifungal compounds. They act by affecting the lipid bilayers of fungal membranes, causing curvature-induced strain and eventual permeabilization. One class of these, known as fengycins, has been commercialized for treating agricultural infections and shows some promise as a possible antifungal pharmaceutical. Understanding the mechanism by which fengycins damage lipid bilayers could prove useful to the future development of related antifungal treatments. In this work, we present multi-microsecond-long simulations of fengycin interacting with different lipid bilayer systems. We see fengycin aggregation and uncover a clear aggregation pattern that is partially influenced by bilayer composition. We also quantify some local bilayer perturbations caused by fengycin binding, including curvature of the lipid bilayer and local electrostatic-driven reorganization.

Simulating the mechanism of antimicrobial lipopeptides with all-atom molecular dynamics.

The emergence of antibiotic resistant pathogens is one of the major medical concerns of the 21st century, prompting renewed interest in the development of novel antimicrobial compounds. Here we use microsecond-scale all-atom molecular dynamics simulations to characterize the structure, dynamics, and membrane-binding mechanism of a synthetic antimicrobial lipopeptide, C16-KGGK. Our simulations suggest that these lipopeptides prefer to aggregate in solution and alter the intrinsic order of the lipid bilayer upon binding. From these results and previous coarse-grained simulations, we have developed a simple model for the binding and insertion process for these lipopeptides.

Characterization of a potent antimicrobial lipopeptide via coarse-grained molecular dynamics.

The prevalence of antibiotic-resistant pathogens is a major medical concern, prompting increased interest in the development of novel antimicrobial compounds. One such set of naturally occurring compounds, known as antimicrobial peptides (AMPs), have broad-spectrum activity, but come with many limitations for clinical use. Recent work has resulted in a set of antimicrobial lipopeptides (AMLPs) with micromolar minimum inhibitory concentrations and excellent selectivity for bacterial membranes. To characterize a potent, synthetic lipopeptide, C16-KGGK, we used multi-microsecond coarse-grained simulations with the MARTINI forcefield, with a total simulation time of nearly 46µs. These simulations show rapid binding of C16-KGGK, which forms micelles in solution, to model bacterial lipid bilayers. Furthermore, upon binding to the surface of the bilayer, these lipopeptides alter the local lipid organization by recruiting negatively charged POPG lipids to the site of binding. It is likely that this drastic reorganization of the bilayer has major effects on bilayer dynamics and cellular processes that depend on specific bilayer compositions. By contrast, the simulations revealed no association between the lipopeptides and model mammalian bilayers. These simulations provide biophysical insights into lipopeptide selectivity and suggest a possible mechanism for antimicrobial action. This article is part of a Special Issue entitled: Membrane protein structure and function.