Many animals have a magnetic sense that tells them North from South. Migratory birds, salmon, or sea turtles migrate thousands of miles relying on this sense, but also animals staying closer to home like honeybees, newts or lobsters use it. Most likely, the animal magnetic sense is based on two types of receptors, one based on magnetite, another one on a protein called cryptochrome found in animal eyes, including human eyes. So why do we humans not enjoy the magnetic sense? A recent report, offers a very intriguing answer. In sensing the Earth's magnetic field, cryoptochrome relies on so-called redox reactions which exchange electrons between molecules. Such reactions are crucial for life, but can also be damaging; antioxidants are used by organisms, but also in pharmacology and as dietary supplements to keep the reactions in check. Apparently, cryptochrome recruits as a reaction partner in its magnetosensitive behavior a special form of molecular oxygen, namely its negatively charged brethren superoxide. For this purpose cryptochrome requires superoxide in low doses, which is good since superoxide, though arising in organisms and used in signaling elsewhere in the body, is actually toxic. The human body has an extremely efficient enzyme, superoxid dismutase, that keeps superoxid at a very low concentration level, apparently too low for human cryptochromes to capture it and tell North from South. Humans, somewhere in evolution, might have lost the magnetic sense, but gained longevity. More on our cryptochrome web site.

Living cells are characterized by a great diversity of separate internal spaces, the boundaries of which are made of membranes forming convoluted surfaces of manifold shapes. Sculpting these shapes is achieved in many cases by proteins. A single protein is too small to bend the membrane into useful shapes, such as spheres or tubes, that measure 10-100 nm, or more, in diameter. Indeed, the proteins work in teams, but exactly how remained a mystery. Now a computational study elucidates the membrane-sculpting process for proteins called amphiphysin N-BAR domain. Simulations performed with NAMD had revealed a first glimpse earlier (see the Sep 2008 highlight). The new study showed that multiple N-BAR domains form lattices maintained through electrostatic interactions. Positively charged, banana-shaped surfaces of individual proteins bend the negatively charged membrane, while the lattice formation ensures a uniform bending force across a wide membrane surface. In a dramatic example of computational "microscopy" the 200 microsecond sculpting of a large flat membrane into a complete tube was observed. More here.

Computational modeling seeks to simulate biomolecules, particularly proteins. The dream of computational biologists is that their simulations realistically mirror the structure and dynamics of proteins, which act as molecular machines in living cells. Indeed, when researchers tried to simulate how a nascent protein folds into its known shape the chosen protein, called WW domain, did not fold properly (see the May 2008 Highlight). Until recently, simulations could follow protein movement for about 0.0000001 seconds and the computational mirror seemed to work well. Recently, however, simulations with the program NAMD began to follow proteins for almost 0.0001 seconds, a thousand times longer, and the mirror showed cracks. Thus, a question arose as to what went wrong and how the distortion could be repaired. It was unclear whether the simulations still did not last long enough, or whether the physical interactions in the protein were poorly described in the computer model that was used. As reported in a recent paper, the interactions show subtle errors, significant enough to throw off the energy balance in the folding protein. Fortunately, the results suggest ways to improve the computation of physical interactions to fold proteins more accurately, repairing the cracks in the mirror. More information is available at our protein folding website.

Many living cells, so-called eukaryotic ones, organize their genetic materials in the cell's nucleus, enveloped by a double membrane with guarded access through pores that involve an amazing filter. Like an ordinary filter it permits passage of small particles (biomolecules), but not of large particles (e.g., proteins). However, certain large particles, proteins called transport receptors, can pass. The filter is made of long "finger" proteins anchored inside the pores. The transport receptors can intermittently widen the filter. But to observe how this is achieved is difficult since the finger proteins are highly disordered. As reported recently, simulations using NAMD suggest now a simple and elegant answer: the finger proteins bundle in groups of 2 - 6 and form a brush, filling with its bristles the nuclear pores. The bristles are bundles of finger proteins and have two key properties: (i) on their surface they are dotted with spots of amino acid pairs, phenylalanine and glycine, that are known to interact favorably with transport receptors (see the Aug 2007 highlight, the Feb 2007 highlight, and the Jan 2006 highlight); (ii) the bristles are also interconnected, namely where finger proteins change from one bundle to another bundle, which they do with some frequency. It appears then that the bristles of the nuclear pore filter form an energetically favorable environment for transport receptors and that the latter can tear a finger protein readily away from a bundle to form a wider space for passage. More information here.

Nanotechnology develops small devices with dimensions below 100 nm, one hundred times smaller than the diameter of a human hair. Nanodevices can be used for a wide range of applications, such as biomedical sensors (see the Jan 2005 highlight) or tools for studying DNA properties (see the Feb 2009 highlight and the Nov 2005 highlight). In building and controlling such small devices, researchers run into problems such as surface effects and significant thermal fluctuations. Furthermore, properties arising from the discrete nature of matter start to dominate at the nanoscale, producing phenomena not observed in larger devices. For instance, when immersed in electrolytic solution and under the influence of an electric field, nanopores act as diodes for ionic currents, conducting in one voltage polarity better than the other, a behavior which has been proposed as the basis for developing nanoelectronic devices. In a recent report, researchers have studied this so-called rectification behavior by means of molecular dynamics simulations using the program NAMD, the ionic rectification inside the nanopore being described in atomic detail. More information can be found here. See also our recent biotechnology review.

All cells making up the human body contain the same DNA in their nucleus, the DNA entailing about 30,000 genes and each gene containing instructions for a protein. Despite this sameness, the cells in different parts of our body are very different due to many factors, a key one being that the level of expression of genes into protein is highly regulated and differs strictly from cell to cell. One rather common regulation mechanism involves methylation of one of the four bases of DNA, cytosin. Researchers find that the long DNA in human cells show spots of methylated cytosins, the methylation being correlated with the expression level of the genes near the spots. In fact, medical researcher relate several cancers to improper methylation of DNA. Despite the common occurrence of regulation by methylation, researchers have little understanding how methylation, that changes an H (hydrogen atom) for a CH_3 (methyl group) here and there, i.e., just adds small bumps on a rather bulky DNA molecule, affect the physical properties of DNA such that expression levels are altered. It was found that there are proteins that can recognize the CH_3 groups, i.e., the bumps, on the DNA, but researchers have a hunch that methylation does affect DNA properties directly, i.e., without protein markers, but do not know which properties. In a collaboration between bioengineers measuring the passing of DNA through nanopores and computational biologists simulating this process with NAMD (see also the Nov 2005 highlight stretchable DNA) first hints emerge that methylation does in fact alter DNA's ability to stretch itself through a nanopore. As reported recently, pulling DNA electrostatically through nanopores is easier for methylated than for unmethylated DNA, as seen both in experiment and simulation. The findings promise insight into an important chapter in the field of genetic control. More on our methylated DNA website. See also our recent biotechnology review.

The ribosome is one of the largest molecular machines present in hundreds to thousands of copies in every cell, in charge of synthesizing every protein in the cell faithfully from genetic instruction. For this purpose the ribosome "reads" the sequence of bases on so-called messenger RNA, three bases at a time and depending on the base triple, the codon, elongates a nascent protein by one of 20 possible amino acids, avoiding to an impressive degree adding a wrong amino acid. So far one knew that the reading is done by transfer RNA molecules that have "foots" which match the possible codons and a "head" that brings along the associated amino acid. Each amino acid has its transfer RNA, the transfer RNAs checking if the next codon is "theirs," and if it is they add the proper amino acid to the nascent protein, elongating it. But how does the ribosome make the critical decision at the decoding center, namely if the transfer RNA "foot," the so-called anticodon, matches the codon? The answer is not known, but a key detail has now been discovered through a combination of electron microscopy and molecular dynamics simulation using NAMD, VMD, and a method called flexible fitting (MDFF, see the June 2008 highlight). It was known that a third molecular system is involved, called the elongation factor Tu (EF-Tu), which generates a key signal to the ribosome and transfer RNA through a chemical reaction. This reaction involves chemically attacking a substrate of EF-Tu, the molecule guanosine-triphosphate (GTP), with water, breaking a bond and turning GTP into guanosine-diphosphate (GDP). The puzzle was that EF-Tu is far away from the decoding center. The collaboration between experiment and simulation, reported here, revealed that "correct recognition" through anticodon-codon binding opens a gate in the EF-Tu that allows water access to the GTP inducing the signaling reaction. The finding promises to now establish how the decision at the decoding center is made and how an "open sesame" order is transmitted to EF-Tu. More on our ribosome website.