Carbon nanotubes are becoming universal tools and building blocks in nanomedicine, being proposed as nanodevices for drug delivery, DNA transfection, and biosensing. They can also be employed as nanopores that conduct protons, ions, and small molecules (see June 2003 highlight), or as reaction vessels for new types of chemical reactions. Studying carbon nanotubes can assist in designing improved nanodevices. One approach to studying nanotubes is furnished by molecular dynamics simulations. However, such simulations must account for one key property of nanotubes, their large polarizability due to the mobility of -electrons over the tube walls. Until recently this polarizability could only be calculated through expensive quantum chemical calculations that could not be linked to simulations imaging molecular processes around carbon nanotubes. Recent studies ( 1 , 2 ) reports now an empirical model that can be efficiently implemented into molecular dynamics simulations to take into account the polarization effect. The model reproduces results of more expensive quantum chemistry calculations very well. A first application of the new model studied the transport of water molecules through nanotubes. Water has a strong dipole moment that polarizes the nanotube wall and, therefore, provides a stringent test for the new methodology.

High-density lipoproteins (HDL), often called "good cholesterol", are protein-lipid particles which circulate in the blood collecting cholesterol from peripheral tissues and transporting them to the liver for degradation. Native HDL are heterogeneous particles which exhibit a variety of shapes and sizes, thus making structural studies of the major protein component apolipoprotein A-I (apo A-I) difficult. However, nanodiscs which are reconstituted discoidal HDL mimics being developed as platforms in which to embed membrane proteins, can be assembled into homogeneous particles. Thus, we utilized the extensive characterization of nanodiscs in furthering our understanding of the structure of apo A-I as well as the assembly of lipoprotein particles. Whereas, the structure of lipoprotein particles can be studied using all-atom molecular dynamics, the long time scales needed for assembly simulations required the development of a coarse grained protein-lipid model.

The most celebrated molecule of living cells, DNA, owes its fame to its role as a carrier of genetic information. But DNA is also impressive through other amazing properties, for example its mechanical flexibility. At first sight, it might seem a dull question to ask what is the smallest pore DNA can be squeezed through, as the obvious answer is that the diameter of that pore should be slightly larger than the diameter of a DNA helix. However, recent studies (paper1, paper2) in asking the stated question discovered that double stranded DNA can permeate, without loosing its structural integrity, pores smaller in diameter than a DNA double helix. The discovery was initiated through molecular dynamics simulations, carried out using NAMD and VMD. The simulations demonstrated that if an electrical field, driving negatively charged DNA through a nanopore, exceeds some critical value, the force exerted on DNA stretches DNA to twice its equilibrium length, reducing thereby its diameter and allowing it to squeeze through narrow pores. The simulations predicted precise values of pore radii and associated critical fields. The predictions were validated experimentally by counting the number of DNA copies that passed at different electric fields through synthetic nanopores. Further details about this study can be found here.

For the sequence of DNA, the genetic instructions of cells, to be read, the double helix of DNA is split open, exposing single DNA strands to DNA binding proteins. Once bound to DNA, the proteins, in carrying out their functions, will crawl along the DNA strand in one of two directions, towards DNA's 3' or 5' end. A recent study of DNA discovered a surprising property of single DNA strands that seems to explain how DNA binding proteins recognize the right direction on DNA strands. By measuring the translocation of DNA through alpha-hemolysin, a membrane protein with a narrow pore, researches discovered that directed single stranded DNA moves much faster when entering the pore 3' end first, rather than 5' end first. The underlying mechanism of this directionality was discovered through molecular dynamics simulations using NAMD and VMD. The simulations revealed that, in a narrow pore, DNA bases tilt collectively towards the 5' end, transforming a wide space directionless DNA brush into a tight space DNA ratchet. The 360,000-atom MD simulation did not only reveal how the DNA bases align and move faster in the "smooth" direction, but did also predict how the directional DNA movement can be discerned by means of direction-sensitive ionic currents through the channel blocked by translocating DNA strands. More details about this study can be found here.

In an optimistic future, cars and appliances will be powered by renewable energy produced by burning hydrogen gas, with water being the only waste product. To supply this hydrogen gas, scientists are turning their attention to an enzyme called hydrogenase that is found in certain microorganisms, which produce hydrogen gas from sunlight and water. This enzyme, however, is sensitive to oxygen gas, which irreversibly deactivates its hydrogen-producing active site. Understanding how oxygen reaches the active site will provide insight into how hydrogenase's oxygen tolerance can be increased through protein engineering, and in turn make hydrogenase an economical source of hydrogen fuel. In a recent paper (also described in this webpage), the programs NAMD and VMD are used to analyze the gas diffusion process inside hydrogenase, and how it correlates with the protein's internal fluctuations, thereby creating a map of the oxygen pathways. The calculations revealed two distinct pathways for oxygen to reach the active site. Gases participate in physiological processes of many organisms and the new computational strategy developed promises to image gas diffusion pathways for many relevant proteins. In fact, the researchers are currently inspecting hundreds of proteins for their ability to internally transport gas molecules.

In a biological cell, membrane channels act like miniature valves regulating the flow of ions and other solutes between intracellular compartments and across the cell's boundary. Assembled in complex circuits, they generate, transmit, and amplify signals orchestrating cell function. To investigate how membrane channels work, life scientists, using an extremely fine pipette, isolate a tiny patch of a cell membrane and, in so-called patch clamp measurements, determine electric currents in response to applied electric potentials. Dramatic increase in computational power and its efficient utilization by NAMD allows one today to reproduce such studies computationally, calculating the permeability of a membrane channel to ions and water directly from its atomic structure. In what is one of the largest molecular dynamics simulation to date, described in a recent paper as well as on our web site (here), one copy of the membrane channel alpha-hemolysin, submerged in a lipid membrane and water, was subject to an external electric field that drove ions and water through the channel. The calculations produced also an image of the electrostatic potential across the channel (see figure).

The biological control of inorganic crystal formation, morphology and assembly is of interest to biologists and biotechnologists studying hard tissue growth and regeneration, as well as to materials scientists using biomimetic approaches for control of inorganic material fabrication and assembly. A molecular-level understanding of the natural mechanisms involved in these processes can be derived from the use of metal surfaces to study surface recognition by proteins together with combinatorial genetics techniques for selection of suitable peptides.

In a recent study, the structure of a genetically engineered gold binding protein has been determined computationally, and the ability of the protein to recognize gold crystal surfaces has been explained. Molecular dynamics simulations were carried out with the program NAMD using the solvated protein at the gold surface to assess the dynamics of the binding process and the effects of surface topography on the specificity of protein binding.

Bionanotechnology involves a marriage of two different materials: inorganic solids, like silica, and biomolecules, like DNA. The new combinations of materials have to be mastered on the laboratory bench as well as in computer simulations. On the bench, devices are manufactured and tested, in the simulations, they are imaged and designed. So far inorganic solids and biomolecules were simulated successfully, but only separately. To join the materials requires as much effort in simulations as on the bench. Even just the interaction of inorganic solids (like silica) with physiological solutions (water and ions) demands challenging descriptions of silica surface properties. As reported recently, researchers have now succeeded in describing accurately the wetting (by water) of amorphous silica, an essential material for nanoelectronics, clearing a major hurdle to simulating bionanotechnological devices, for example, those suggested for rapid and economical sequencing of DNA (see also Nov 2005 and Oct 2004 highlights). More on silica-water interaction here.