Carbon dioxide (CO 2 ) movement across cellular membranes is passive and governed by Fick's law of diffusion. Until recently, we believed that gases cross biological membranes exclusively by dissolving in and then diffusing through membrane lipid. However, the observation that some membranes are CO 2 impermeable led to the discovery of a gas molecule moving through a channel; namely, CO 2 diffusion through aquaporin-1 (AQP1). Later work demonstrated CO 2 diffusion through rhesus (Rh) proteins and NH 3 diffusion through both AQPs and Rh proteins. The tetrameric AQPs exhibit differential selectivity for CO 2 versus NH 3 versus H 2 O, reflecting physico-chemical differences among the small molecules as well as among the hydrophilic monomeric pores and hydrophobic central pores of various AQPs. Preliminary work suggests that NH 3 moves through the monomeric pores of AQP1, whereas CO 2 moves through both monomeric and central pores. Initial work on AQP5 indicates that it is possible to create a metal-binding site on the central pore's extracellular face, thereby blocking CO 2 movement. The trimeric Rh proteins have monomers with hydrophilic pores surrounding a hydrophobic central pore. Preliminary work on the bacterial Rh homologue AmtB suggests that gas can diffuse through the central pore and three sets of interfacial clefts between monomers. Finally, initial work indicates that CO 2 diffuses through the electrogenic Na/HCO 3 cotransporter NBCe1. At least in some cells, CO 2 -permeable proteins could provide important pathways for transmembrane CO 2 movements. Such pathways could be amenable to cellular regulation and could become valuable drug targets.

Biological membranes and their diverse lipid constituents play key roles in a broad spectrum of cellular and physiological processes. Characterization of membrane-associated phenomena at a microscopic level is therefore essential to our fundamental understanding of such processes. Due to the semi-fluid and dynamic nature of lipid bilayers, and their complex compositions, detailed characterization of biological membranes at an atomic scale has been refractory to experimental approaches. Computational modeling and simulation offer a highly complementary toolset with sufficient spatial and temporal resolutions to fill this gap. Here, we review recent molecular dynamics studies focusing on the diversity of lipid composition of biological membranes, or aiming at the characterization of lipid-protein interaction, with the overall goal of dissecting how lipids impact biological roles of the cellular membranes.

The march toward exascale computing will enable routine molecular simulation of larger and more complex systems, for example, simulation of entire viral particles, on the scale of approximately billions of atomsa simulation size commensurate with a small bacterial cell. Anticipating the future hardware capabilities that will enable this type of research and paralleling advances in experimental structural biology, efforts are currently underway to develop software tools, procedures, and workflows for constructing cell-scale structures. Herein, we describe our efforts in developing and implementing an efficient and robust workflow for construction of cell-scale membrane envelopes and embedding membrane proteins into them. A new approach for construction of massive membrane structures that are stable during the simulations is built on implementing a subtractive assembly technique coupled with the development of a structure concatenation tool (fastmerge), which eliminates overlapping elements based on volumetric criteria rather than adding successive molecules to the simulation system. Using this approach, we have constructed two “protocells” consisting of MARTINI coarse-grained beads to represent cellular membranes, one the size of a cellular organelle and another the size of a small bacterial cell. The membrane envelopes constructed here remain whole during the molecular dynamics simulations performed and exhibit water flux only through specific proteins, demonstrating the success of our methodology in creating tight cell-like membrane compartments. Extended simulations of these cell-scale structures highlight the propensity for nonspecific interactions between adjacent membrane proteins leading to the formation of protein microclusters on the cell surface, an insight uniquely enabled by the scale of the simulations. We anticipate that the experiences and best practices presented here will form the basis for the next generation of cell-scale models, which will begin to address the addition of soluble proteins, nucleic acids, and small molecules essential to the function of a cell.

Membrane transporters mediate one of the most fundamental processes in biology. They are the main gatekeepers controlling active traffic of materials in a highly selective and regulated manner between different cellular compartments demarcated by biological membranes. At the heart of the mechanism of membrane transporters lie protein conformational changes of diverse forms and magnitudes, which closely mediate critical aspects of the transport process, most importantly the coordinated motions of remotely located gating elements and their tight coupling to chemical processes such as binding, unbinding and translocation of transported substrate and cotransported ions, ATP binding and hydrolysis, and other molecular events fueling uphill transport of the cargo. An increasing number of functional studies have established the active participation of lipids and other components of biological membranes in the function of transporters and other membrane proteins, often acting as major signaling and regulating elements. Understanding the mechanistic details of these molecular processes require methods that offer high spatial and temporal resolutions. Computational modeling and simulations technologies empowered by advanced sampling and free energy calculations have reached a sufficiently mature state to become an indispensable component of mechanistic studies of membrane transporters in their natural environment of the membrane. In this article, we provide an overview of a number of major computational protocols and techniques commonly used in membrane transporter modeling and simulation studies. The article also includes practical hints on effective use of these methods, critical perspectives on their strengths and weak points, and examples of their successful applications to membrane transporters, selected from the research performed in our own laboratory.

The efficiency of conventional techniques used to harvest energy in nuclear reactors lies around 35%. This limit exists, because the nuclear energy is converted to electrical energy via heat engines. We study an alternative approach where the kinetic energy of nuclear reaction products is directly converted into electric energy in a stack of charged capacitors with a gap size of 500 nm and graphene electrodes. Graphene is expected to be chemically and mechanically stable in high‐radiation environments, because its tensile strength of 130 GPa is very large, about 100 times larger than most metals. The dielectric strength of such nanocapacitors exceeds 1 GV/m, because avalanching is suppressed at small gap sizes. In a 1 GV/m electric field charged nuclear reaction products, such as 5.6 MeV alpha particles, come to rest in of a stack with 5000 nanocapacitors. We show that during the deceleration process more than 90% of kinetic energy of charged nuclear reaction products is converted to electric energy and stored as electric energy in the stack. Each stack is 2.5‐mm thick and produces a high‐voltage DC current. A device with a 1‐Ci241Am source is expected to generate 22 mW of electric power.