Coarse-grained (CG) simulations have become an essential tool to study a large variety of biomolecular processes, exploring temporal and spatial scales inaccessible to traditional models of atomistic resolution. One of the major simplifications of CG models is the representation of the solvent, which is either implicit or modeled explicitly as a van der Waals particle. The effect of polarization, and thus a proper screening of interactions depending on the local environment, is absent. Given the important role of water as a ubiquitous solvent in biological systems, its treatment is crucial to the properties derived from simulation studies. Here, we parameterize a polarizable coarse-grained water model to be used in combination with the CG MARTINI force field. Using a three-bead model to represent four water molecules, we show that the orientational polarizability of real water can be effectively accounted for. This has the consequence that the dielectric screening of bulk water is reproduced. At the same time, we parameterized our new water model such that bulk water density and oil/water partitioning data remain at the same level of accuracy as for the standard MARTINI force field. We apply the new model to two cases for which current CG force fields are inadequate. First, we address the transport of ions across a lipid membrane. The computed potential of mean force shows that the ions now naturally feel the change in dielectric medium when moving from the high dielectric aqueous phase toward the low dielectric membrane interior. In the second application we consider the electroporation process of both an oil slab and a lipid bilayer. The electrostatic field drives the formation of water filled pores in both cases, following a similar mechanism as seen with atomistically detailed models. Many biomolecular processes involve charged species moving between regions of high polarity, such as the water phase, and regions of lower polarity, such as the lipid membrane. Due to the change in electrostatic screening between these two environments, the strength of the interactions between the moving charge and the surrounding molecules also changes. This has important consequences for the way biological activity is controlled. To help understand the forces driving the movement of biomolecules, we developed a computational model which is capable of describing these processes at near-atomic detail. To do so efficiently, we use a coarse-grained description of the molecules, in which some of the atomistic detail is averaged out. To capture the inhomogeneous nature of the dielectric response, we re-introduce some detail in the water model; the new model effectively mimics the orientational polarizability of real water molecules, and screens electrostatic interactions realistically. This enables the study of a number of important biological processes that were hitherto considered challenging for coarse-grained models, such as the permeation of ions across a lipid membrane and the rupture of membranes due to an electrostatic field, at relatively low computational cost.

The distribution of phospholipids across the inner membrane (IM) of Gram-negative bacteria is unknown. We demonstrate that the IMs of Escherichia coli and Yersinia pseudotuberculosis are asymmetric, with a 75%/25% (cytoplasmic/periplasmic leaflet) distribution of phosphatidylethanolamine (PE) in rod-shaped cells and an opposite distribution in E. coli filamentous cells. In initially filamentous PE-lacking E. coli cells, nascent PE appears first in the periplasmic leaflet. As the total PE content increases from nearly zero to 75%, cells progressively adopt a rod shape and PE appears in the cytoplasmic leaflet of the IM. The redistribution of PE influences the distribution of the other lipids between the leaflets. This correlates with the tendency of PE and cardiolipin to regulate antagonistically lipid order of the bilayer. The results suggest that PE asymmetry is metabolically controlled to balance temporally the net rates of synthesis and translocation, satisfy envelope growth capacity, and adjust bilayer chemical and physical properties.

The composition of the plasma membrane of malignant cells is thought to influence the cellular uptake of cisplatin and to take part in developing resistance to this widespread anti-cancer drug. In this work we study the permeation of cisplatin through the model membranes of normal and cancer cells using molecular dynamics simulations. A special attention is paid to lipid asymmetry and cholesterol content of the membranes. The loss of lipid asymmetry, which is common for cancer cells, leads to a decrease in their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change in the cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5–6 orders of magnitude higher than one of the membranes with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

Once introduced in the organism, the interaction of nanoparticles with various biomolecules strongly impacts their fate. Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of cancer cells with high LP receptors expression.In vitroandin vivoexperiments reveal preeminent affinity of the squalene-gemcitabine bioconjugates towards LP particles with the highest cholesterol content andin silicosimulations further display their incorporation into the hydrophobic core of LPs. To the best of our knowledge, the use of squalene to induce drug insertion into LPs for indirect cancer cell targeting is a novel concept in drug delivery. Interestingly, not only SQGem but also other squalene derivatives interact similarly with lipoproteins while such interaction is not observed with liposomes. The conjugation to squalene represents a versatile platform that would enable efficient drug delivery by simply exploiting endogenous lipoproteins.

In this work we conduct a systematic analysis of the influence of curvature on various properties of a realistic model of mammalian plasma membrane with asymmetric lipid content of monolayers and a realistic concentration of cholesterol. In order to do this we developed new technique for simulating membranes with the global membrane curvature restricted to any desirable value while keeping free lateral diffusion of the lipids and without introducing artifacts or perturbing the membrane structure. We show that the thickness of the hydrophobic core of the concave monolayer decreases by approximately 1.3 Å in comparison to that of the flat membrane, while the thickness of the convex monolayer does not change. The order parameter of the lipid tails decreases significantly in the certain layers of the curved membrane. The area per lipid increases in the convex monolayer and decreases in the concave monolayer. The cholesterol inclination angle decreases when the curvature of a particular monolayer changes from concave to convex. The amount of cholesterol in the minor fraction located between the membrane leaflets is zero in the membrane with positive curvature and increases to 1.7% in the flat membrane and to 2.5% in the membrane with negative curvature.