Atomistic molecular dynamics simulations have become an important source of information for the structure and dynamics of biomembranes at molecular detail difficult to access in experiments. A number of force fields for lipid membrane simulations have been derived in the past; the choice of the most suitable force field is, however, frequently hampered by the availability of parameters for specific lipids. Additionally, the comparison of different quantities among force fields is often aggravated by varying simulation parameters. Here, we compare four atomistic lipid force fields, namely, the united-atom GROMOS54a7 and the all-atom force fields CHARMM36, Slipids, and Lipid14, for a broad range of structural and dynamical properties of saturated and monounsaturated phosphatidylcholine bilayers (DMPC and POPC) as well as for monounsaturated phosphatidylethanolamine bilayers (POPE). Additionally, the ability of the different force fields to describe the gel-liquid crystalline phase transition is compared and their computational efficiency estimated. Moreover, membrane properties like the water flux across the lipid bilayer and lipid acyl chain protrusion probabilities are compared.

A system based on two designed peptides, namely the cationic peptide K, (KIAALKE) 3 , and its complementary anionic counterpart called peptide E, (EIAALEK) 3 , has been used as a minimal model for membrane fusion, inspired by SNARE proteins. Although the fact that docking of separate vesicle populations via the formation of a dimeric E/K coiled-coil complex can be rationalized, the reasons for the peptides promoting fusion of vesicles cannot be fully explained. Therefore it is of significant interest to determine how the peptides aid in overcoming energetic barriers during lipid rearrangements leading to fusion. In this study, investigations of the peptides' interactions with neutral PC/PE/cholesterol membranes by fluorescence spectroscopy show that tryptophan-labeled K* binds to the membrane (K K*~6 .2 10 3 M À1 ), whereas E* remains fully water-solvated. 15 N-NMR spectroscopy, depth-dependent fluorescence quenching, CD-spectroscopy experiments, and MD simulations indicate a helix orientation of K* parallel to the membrane surface. Solid-state 31 P-NMR of oriented lipid membranes was used to study the impact of peptide incorporation on lipid headgroup alignment. The membrane-immersed K* is found to locally alter the bilayer curvature, accompanied by a change of headgroup orientation relative to the membrane normal and of the lipid composition in the vicinity of the bound peptide. The NMR results were supported by molecular dynamics simulations, which showed that K reorganizes the membrane composition in its vicinity, induces positive membrane curvature, and enhances the lipid tail protrusion probability. These effects are known to be fusion relevant. The combined results support the hypothesis for a twofold role of K in the mechanism of membrane fusion: 1) to bring opposing membranes into close proximity via coiled-coil formation and 2) to destabilize both membranes thereby promoting fusion.

Biological cells and their organelles are protected by ultra thin membranes. These membranes accomplish a broad variety of important tasks like separating the cell content from the outer environment, they are the site for cell-cell interactions and many enzymatic reactions, and control the in- and efflux of metabolites. For certain physiological functions e.g. in the fusion of membranes and also in a number of biotechnological applications like gene transfection the membrane integrity needs to be compromised to allow for instance for the exchange of polar molecules across the membrane barrier. Mechanisms enabling the transport of molecules across the membrane involve membrane proteins that form specific pores or act as transporters, but also so-called lipid pores induced by external fields, stress, or peptides. Recent progress in the simulation field enabled to closely mimic pore formation as supposed to occur in vivo or in vitro. Here, we review different simulation-based approaches in the study of membrane pores with a focus on lipid pore properties such as their size and energetics, poration mechanisms based on the application of external fields, charge imbalances, or surface tension, and on pores that are induced by small molecules, peptides, and lipids. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg.

A molecular description of the lipid-protein interactions underlying the adsorption of proteins to membranes is crucial for understanding, for example, the specificity of adsorption or the binding strength of a protein to a bilayer, or for characterizing protein-induced changes of membrane properties. In this paper, we extend an automated in silico assay (DAFT) for binding studies and apply it to characterize the adsorption of the model fusion peptides E and K to a mixed phospholipid/cholesterol membrane using coarse-grained molecular dynamics simulations. In addition, we couple the coarse-grained protocol to reverse transformation to atomistic resolution, thereby allowing to study molecular interactions with high detail. The experimentally observed differential binding of the peptides E and K to membranes, as well as the increased binding affinity of helical over unstructered peptides, could be well reproduced using the polarizable Martini coarse-grained (CG) force field. Binding to neutral membranes is shown to be dominated by initial binding of the positively charged N-terminus to the phospholipid headgroup region, followed by membrane surface-aligned insertion of the peptide at the interface between the hydrophobic core of the membrane and its polar headgroup region. Both coarse-grained and atomistic simulations confirm a before hypothesized snorkeling of lysine side chains for the membrane-bound state of the peptide K. Cholesterol was found to be enriched in peptide vicinity, which is probably of importance for the mechanism of membrane fusion. The applied sequential multiscale method, using coarse-grained simulations for the slow adsorption process of peptides to membranes followed by backward transformation to atomistic detail and subsequent atomistic simulations of the preformed peptide-lipid complexes, is shown to be a versatile approach to study the interactions of peptides or proteins with biomembranes.

Biological cells are enveloped by a heterogeneous lipid bilayer that prevents the uncontrolled exchange of substances between the cell interior and its environment. In particular, membranes act as a continuous barrier for salt and macromolecules to ensure proper physiological functions within the cell. However, it has been shown that membrane permeability strongly depends on temperature and, for phospholipid bilayers, displays a maximum at the transition between the gel and fluid phase. Here, extensive molecular dynamics simulations of dipalmitoylphosphatidylcholine bilayers were employed to characterize the membrane structure and dynamics close to phase transition, as well as its stability with respect to an external electric field. Atomistic simulations revealed the dynamic appearance and disappearance of spatially related nanometer-sized thick ordered and thin interdigitating domains in a fluid-like bilayer close to the phase transition temperature (T m). These structures likely represent metastable precursors of the ripple phase that vanished at increased temperatures. Similarly, a two-phase bilayer with coexisting gel and fluid domains featured a thickness minimum at the interface because of splaying and interdigitating lipids. For all systems, application of an external electric field revealed a reduced bilayer stability with respect to pore formation for temperatures close to T m. Pore formation occurred exclusively in thin interdigitating membrane nanodomains. These findings provide a link between the increased membrane permeability and the structural heterogeneity close to phase transition.