Proteins carry out most functions in living cells, from import of food substances to chemical synthesis to motion to signaling. Proteins are chains of amino acids like GLSDGEWQLVLNVWGKVEAD... where each letter stands for one of twenty amino acids that are the building blocks of proteins, i.e., G for glycine or L for leucine. In general, sequences of proteins native to cells fold into unique three-dimensional structures capable of executing the proteins' specific function. Living cells store the amino acid sequences of their many different proteins in the form of DNA sequences, safeguarding them in the cells genome. On demand, the DNA sequences are translated according to the famous genetic code into amino acid sequences. The amino acid chains of newly synthesized proteins have to fold into the proper structure, an essential process scrutinized by biologists for decades. The folding process often takes milliseconds or longer, but recently proteins were identified that fold within microseconds. This was still a time too long to be simulated through molecular dynamics which could reveal folding in atomic level detail. However, improvements of NAMD have now made simulations of 10 microseconds possible and in a recent report experimental and computational biologists describe a joint study of a protein segment, known as the WW domain, over this timescale. The great increase in simulation time revealed intricate details of WW domain folding, but also points to a need to further improve the computational model (force field) used to simulate proteins. See also our protein folding web site.

Adhesion between human cells organizes our body into its organs and parts. The adhesion comes about through an intricate system of molecules that perform their task in a highly selective manner such that the body's different types of cells will find the right cells and stick to them. This selectivity leads to tissue differentiation and the organization of organs as complicated as the brain. Cadherin proteins form a particular family of such adhesion molecules. Interestingly, they glue cells together only in the presence of calcium. Some members of the cadherin family of proteins are also involved in the transduction of sound and cadherin mutants are known to cause hereditary deafness (see the April 2005 highlight, "Hearing: Turning Sound into Voltage"). How cadherins selectively bind to each other and the role of calcium was not well understood, but now molecular dynamics simulations have offered magnificent insight into calcium's role as recently reported. The simulations took advantage of parallel supercomputers and NAMD's ability to harness their power. The simulations revealed that in the absence of calcium cadherins stick out of cell surfaces like ends of loose rope; in the presence of calcium cadherin molecules turn into stiff hooks that link cells together. The calcium-induced links can withstand the strong mechanical forces that arise between cells much larger than cadherin (more on our cadherin website).

The environment of cells can undergo drastic changes, for example from dry to wet, in which case cells shrivel or swell. However, they are protected from bursting by a system of safety valves in their cellular membranes that open and release cellular content. Some of the valves open already at low membrane tension, but only little, others open only at higher tension, but wide and without filtering outflow. The mechanosensitive channel of small conductance, MscS, is a low pressure safety valve in bacterial cells (see the Feb 2007 highlight, "Observing and Modeling a Crucial Membrane Channel", the May 2006 highlight, "Electrical Safety Valve", and the Nov 2004 highlight, "Japanese Lantern Protein"). MscS is able to rescue cells about to burst by releasing small solutes through a large and transient opening in the cell membrane, thereby relieving internal pressure. The only way to learn how MscS performs this vital task is by determining its atomic-level structure under native conditions. However, the only structure available for MscS was obtained for the purified and crystallized protein; inspection of the structure left doubt that it shows a functional protein, i.e., a closed safety valve. Now a team of experimentalists and modelers report the structure of MscS seen in its natural membrane environment. In their approach, simulations incorporate information from so-called paramagnetic resonance measurements experiments. This finding is yet another case where the combination of modeling and observation offers entirely new close-up views of living cells (more on our MscS website).

Bleeding through physical injury is stopped in animals through the formation of blood clots. Such clots, actually arising often in blood vessels without injury, can rupture due to the blood's shear forces and obstruct upstream smaller vessels leading to life threatening stroke, pulmonary embolism, and heart attack. Hence, a blood clot must be both mechanically stable to stop bleeding, yet elastic enough to avoid rupture. Fibrin, the main component of a blood clot, possesses the stated mechanical properties in healthy individuals, but in pathological circumstances needs to be managed through medication. Unfortunately, preventive treatment of blood clots is still a black art since the molecular basis of fibrin elasticity is unknown. Clinicians at the Mayo Clinic teamed up with computational biologists at the University of Illinois to investigate this elasticity, focusing on the protein fibrinogen, the building block of fibrin. The clinical researchers stretched individual fibrinogen molecules measuring the force needed to extend the molecules. They found a characteristic force - extension relationship and its dependence on blood pH and calcium concentration, but they could not interpret the finding chemically, a prerequisite for improving blood clot chemical management. The clinical researchers joined forces with computational biologists who could reproduce the measured force - extension relationship in steered molecular dynamics using NAMD. The simulations starting from known crystallographic structures of fibrinogen offered a full, i.e., atom resolution, chemical picture of fibrinogen elasticity. As reported recently by the clinical and computational researchers the insight gained opens new avenues for blood clot treatment. For example, it was found that pH and calcium concentrations alter the stiffness of blood clots, thereby opening pharmacological avenues for controlling the incidence of pathological blood clots. More on this investigation can be found here.

Biological cells protect their interior through their cellular membranes, yet rely on import of nutrients. They have evolved for this import fast conduction channels that include reliable checkpoints distinguishing desirable and undesirable compounds. A checkpoint puts up a veritable obstacle course that only the right compounds can pass quickly. Understanding the channel design is difficult due to lack of detailed experimental data on nutrient dynamics. Presently, the most detailed information comes from viewing channel dynamics computationally, starting from static crystallographic structures. A recent study investigated how glycerols, small nutrient molecules needed by some bacteria, pass through checkpoints realized through the membrane protein aquaporin (see also highlights Gas Molecules Commute into Cell - Mar 2007, Aquaporin and the Cambridge Five - Oct 2006, Cellular Faucets - Feb 2006). Aquaporin furnishes four parallel channels that were monitored computationally using NAMD and a novel algorithm that explores the channel energetics quickly enough to be methodologicaly feasible on today's computers. The results show how the physical characteristics of glycerol, for example the molecule's ability to form so-called hydrogen bonds, its electrical dipole moments, its diffusive mobility and intrinsic flexibility are probed along the channel, discriminating glycerol from other molecules. More on computational investigations of aquaporin here.