The importance of membrane defects-lessons from simulations.

The defects and pores within lipid membranes are scientifically interesting and have a number of biological applications. Although lipid bilayers are extremely thin hydrophobic barriers, just ∼3 nm thick, they include diverse chemistry and have complex structures. Bilayers are soft and dynamic, and as a result, they can bend and deform in response to different stimuli by means of structural changes in their component lipids. Though defects occur within these structures, their transience and small size have made it difficult to characterize them. However, with recent advances in computer power and computational modeling techniques, researchers can now use simulations as a powerful tool to probe the mechanism and energies of defect and pore formation in a number of situations. In this Account, we present results from our detailed molecular dynamics computer simulations of hydrophilic pores and related defects in lipid bilayers at an atomistic level. Electroporation can be used to increase the permeability of cellular membranes, with potential therapeutic applications. Atomistic simulations of electroporation have illustrated the molecular details of this process, including the importance of water dipole interactions at the water-membrane interface. Characterization of the lipid-protein interactions provides an important tool for understanding transmembrane protein structure and thermodynamic stability. Atomistic simulations give a detailed picture of the free energies of model peptides and side chains in lipid membranes; the energetic cost of defect formation strongly influences the energies of interactions between lipids and polar and charged residues. Many antimicrobial peptides form hydrophilic pores in lipid membranes, killing bacteria or cancer cells. On the basis of simulation data, at least some of these peptides form defects and pores near the center of the bilayer, with a common disordered structure where hydrated headgroups form an approximately toroidal shape. The localization and trafficking of lipids supports general membrane structure and a number of important signaling cascades, such as those involving ceramide, diacylglycerol, and cholesterol. Atomistic simulations have determined the rates and free energies of lipid flip-flop. During the flip-flop of most phosphatidylcholine lipids, a hydrophilic pore forms when the headgroup moves near the center of the bilayer. Simulations have provided novel insight into many features of defects and pores in lipid membranes. Simulation data from very different systems and models show how water penetration and defect formation can determine the free energies of many membrane processes. Bilayers can deform and allow transient defects and pores when exposed to a diverse range of stimuli. Future work will explore many aspects of membrane defects with increased resolution and scope, including the study of more complex lipid mixtures, membrane domains, and large-scale membrane remodeling. Such studies will examine processes including vesicle budding and fusion, non-bilayer lipid phases, and interactions between lipid bilayers and other biomolecules. Simulations provide information that complements experimental studies, allowing microscopic insight into experimental observations and suggesting novel hypotheses and experiments. These studies should enable a deeper understanding of the role of lipid bilayers in cellular biology and support the development of future lipid-based biotechnology.