Bacterial cells, like those of Escherichia coli, protect themselves against sudden inside-out pressure differences that arise osmotically from changes in a cell's environment and that could burst the cellular envelop. The protection is achieved through so-called mechanosensitive channels in the cell membrane.  One such channel, that dissipates like a safety valve pressure differences across the Escherichia coli cell membrane, is contributed by the protein MscS.  Upon tension in the cell membrane, that can also be applied systematically in the laboratory, the channel opens and permits molecules to pass, as best measured through an ion current leaking through the stretched membrane.  MscS is a channel with a balloon-like filter,  the function of the latter being still a mystery  (see Nov 2004 highlight, "Japanese lantern protein").  Now computational biologists using NAMD teamed up with device engineers using BioMoca to study MscS as reported recently.  The team monitored the mysterious MscS computationally over several microseconds, a record time for protein simulations.  MscS was found to permit water passage, but to also exhibit strong electrostatic forces that focus ions streaming through its filter balloon and channel.  This suggests MscS to be both a hydrostatic and an electrical safety valve.  Even though now better known, MscS' entire function remains shrouded in mystery (more on our MscS web site).

When Escherichia coli bacteria enjoy lactose and related food molecules in their environment, the cells quickly furnish proteins needed for import and metabolic digestion of the food. A set of genes, called the lac operon, is transcribed into messenger RNA that directs the synthesis of these proteins. When lactose is not available, the protein synthesis would be wasteful and, indeed, is prevented by locking the lac operon. This is achieved by a protein called lac repressor that forces the segment of the lac operon needed to initiate transcription into a loop, but that can be unlocked by a lactose molecule binding to the protein as soon as the food becomes available again. A recent study of the lac repressor combines a 314,000-atom protein simulation using NAMD with a multiscale simulation technique coupling the protein to the DNA loop. The calculations reveal how the lac repressor stretches out two "hands" grabbing the genomic DNA and then keeps a tight grip on the DNA wrestling it into a loop. The discovery is described on our website as well as in a popular article.

Muscle fibers are not rigid structures, but rather, they can both contract and extend in response to physiological demand. As a result, muscle sarcomeres must have a protective mechanism to prevent tearing and damage from overstretching. The giant protein titin fulfills this role by acting as a molecular rubber band, providing a passive resistance force during extension to restore the muscle fiber to its resting length. Conceivably, this rubber band must be anchored to a rigid structure in order to function. Biochemical investigations have speculated that the protein telethonin, located at the sarcomeric Z-disc, may serve this purpose. Genetic diseases related to defects in telethonin have been correlated with dilated cardiomyopathy and a form of muscular dystrophy. To date there have been no studies to determine how strongly bound titin is to telethonin. To explore this issue, we performed molecular dynamics simulations in order to test the strength of the newly resolved titin Z1Z2-telethonin complex. Our results, which have recently been reported (paper), reveal that the force required to dissociate titin from telethonin is significantly higher than that required to unfold isolated titin Ig-domains. This suggests strongly that telethonin is in fact an essential component of the Z-disc titin anchor. In addition, we find that telethonin anchors not just one, but two separate titin molecules, serving as a sort of molecular glue joining both titin molecules together through β-strand crosslinking (a structural motif also seen in fibril pathologies such as Alzheimer's, Parkinson, and Huntington's disease). Thus our simulations reveal also a fundamental architectural element of living cells, namely how cells glues their components together yielding strong mechanical connections. For more information on teletonin and the implications of our findings, see the following webpage here.

The ear is a sensitive and robust device, able to perceive the faint sound of flowing water and the thunderous blast of an air plane. Like a microphone, the ear transforms a complex, mechanical stimulus (sound), into an electrical signal, a voltage change in a nerve cell, that can be understood by our brain. This transformation is called "mechanotransduction" and is accomplished by a series of amazingly minute devices that each connect a soft spring to an ion channel, both located in specialized sensory cells, the hair cells of the inner ear. The springs, through their vibrations agitated by particular sound frequencies, control ion currents passing through the channels, thereby, modifying the hair cell internal electrical potential. This leads to neural signaling to the acoustic cortex of the brain. Recently reported molecular dynamics simulations using NAMD, some of the most extensive simulations accomplished to date both in size and duration, showed that the mechanical characteristics of hair cell signaling can be traced to a single protein, ankyrin, that acts as a helical spring. Imagine a soft spring that is extended several inches by the weight of a feather! Ankyrin is such a spring, but a billion times finer.

Cells constitute only part of animal tissue, much of tissue is made of the extracellular matrix (ECM), a flexible mesh composed of several classes of macromolecule. Fibronectin (FN) is a component of the ECM that acts as a specific adhesive, forming networks that connect cells to the giant fibrous molecules that make up the majority of the ECM. Proper FN fibril formation is required to maintain prop er cell migration, thus FN plays roles in diseases affecting growth, development, tumors , and wound healing. We have used SMD simulations to examine how the mechanical force s present in the ECM affect FN fibril formation.

Actin protein units form filaments in the cells in order to manage the cellular shape changes, cell locomotion and chemotactic migration. The mechanical properties of the filaments substantially depend on the ATP hydrolysis by actin. Using molecular dynamics, we studied the ATP hydrolysis and the subsequent release of the inorganic phosphate.

A coarse-grained method of DNA modeling has been developed as a stepping-stone towards a multi-resolution approach to biomolecular modeling. The DNA structure is obtained after numerically solving a Kirchhoff system of equations, augmented with electrostatic and steric repulsion force terms. The method has been applied to restore the missing structure of a DNA loop clamped by the lac repressor.

The giant muscle protein titin, also known as connectin, is a roughly 30,000 amino acid long filament which plays a number of important roles in muscle contraction and elasticity. To examine in atomic detail the dynamics and structure-function relationships of this behavior, SMD simulations of force-induced titin Ig domain unfolding were performed.

The discovery of the crystal structure of the kinesin motor domain has made it possible to study kinesin's dynamics by computer simulations. To model pH- and nucleotide-dependent changes in the kinesin structure, we carried out conformational searches by simulated annealing. The conformational differences of the ATP-bound protein relative to the ADP-bound state can be attributed to a force-producing power stroke.

DNA with its famous double helix structure stores the genetic information of all life forms known. In order that this information is read, the double helix needs to be first unwound and separated into single helices or strands. This is achieved by cellular motor proteins called helicases that operate on already separated DNA strands. The helicases specialize in unwinding and separating the DNA double helix by scooting along one of DNA's single strands against the point where the two strands merge into the double helix; pushing against this point unwinds and separates the double helix further. The helicases are driven by energy stored in molecules of ATP which bind to the protein and get released in their so-called hydrolyzed, lower energy, form. Based on atomic resolution structures, researchers have studied now one of the smallest helicases known, PcrA, from the electronic to the functional level carrying out quantum mechanical/molecular mechanical simulations (as described in a first publication), as well as a combination of classical molecular dynamics simulation, using NAMD, and stochastic modeling calculations (described in a second publication). This resulted in an overall explanation of how ATP's hydrolysis powers helicase activity which has been reported in a third publication. The researchers discovered that PcrA moves with two "hands" along single stranded DNA; when ATP binds, one "hand" moves along the DNA; when ADP and Pi (the hydrolysis products of ATP) unbind, the other "hand" moves; through a molecular "trick" both "hands" move in the same direction. Amazingly, the hand movement arises mainly from an increase in random mobility of the hands. i.e., is not enforced. Physicists refer to the underlying mechanism as a ratchet mechanism that was indeed long suspected to drive molecular motors. Interestingly, the helicase motor is very closely related to a wide class of other biological motors, for example the FoF1-ATP synthase (see Mar 2004 and Nov 2004 highlights). For more information visit our helicase research website.

The bacterial flagellum is a large biomolecular assembly used by many types of bacteria as a helical propeller for forward swimming and turning. The flagellum is remarkable in that its properties differ greatly depending on the direction in which it is rotated, allowing the bacterium to switch between swimming straight ("running") and turning ("tumbling"). The mechanics of the flagellum are of interest both to biologists and mechanical engineers. The molecular mechanisms of the transition in the flagellum between running and tumbling modes is unknown. Because of the flagellum's size (several micrometers in length) and composition (made up of 30,000 protein subunits) it presents a challenge to computational modeling. Researchers have now achieved an advance describing the flagellum in both its running and tumbling state. For this purpose, the researchers developed a computational model of the system that glosses over atomic level detail, but resolves the shapes of all proteins making up a bacterial flagellum, simulating a simplified version of the system using the program NAMD. The results, reported recently, showed that the flagellum's transition between swimming straight and tumbling is triggered by friction due to the water around the bacterium. More information on the flagellum project can be found here.

Mammalian cells adhere to each other forming tissues. The adhesion is due to a network of proteins, so-called extracellular matrix proteins, "gluing" the cells together. The cell membranes are too soft to provide anchoring points for the extracellular matrix proteins; rather, the cells furnish on their outer surface specialized hooks for anchoring the extracellular matrix proteins. The hooks, in the form of surface proteins, are linked directly through the membranes to the intracellular cytoskeleton that stabilizes and shapes cells. Integrins are an important family of such surface proteins that form hooks specific for certain types of extracellular matrix proteins. The hooks are flexible, they can be open for contacts or closed, the switch being induced by signals from inside or outside the cell through interactions with other proteins. The interactions between integrins and extracellular matrix proteins are rather complex, as the proteins are composed of many subunits; fortunately, their overall structures are presently being solved through crystallography. In a recent report a major component of an integrin and an extracellular matrix protein have been investigated through molecular modeling using NAMD, including steered molecular dynamics. The study described in detail how the extracellular matrix protein induces a transition in integrin, potentially strengthening its adhesion property. See also previous highlights: the May 2006 "Killer's Entry Route", Dec 2004 "Snap Fastener on Biological Cells", Dec 2003 "Body's Glue", and Mar 2002 "Cells Sense Push and Pull". More on modeling of extracellular matrix proteins and integrins can be found here.