Highlights of our Work
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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.
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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).
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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).
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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.
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