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ScienceWeek
SCIENCEWEEK
ScienceWeek
November 29, 2002
Vol. 6 Number 48
An Online Research Digest Published Weekly Since 1997
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What does it matter to Science if her passionate servants are
rich or poor, happy or unhappy, healthy or ill? She knows that
they have been created to seek and to discover, and that they
will seek and find until their strength dries up at its source.
It is not in a scientist's power to struggle against his
vocation: even on his days of disgust or rebellion his steps lead
him inevitably back to his laboratory apparatus.
-- Eve Curie (1904-?)
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Section 1
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1. ON PROTEIN FOLDING DYNAMICS.
New protein-folding computational predictions are in excellent
agreement with experimentally determined mean folding times and
equilibrium constants for a small designed protein. The rapid
folding is apparently due to the swift formation of secondary
structure.
2. ON HABITATS AND ECOLOGICAL SPECIATION
Understanding speciation processes in rainforests is key to
predicting changes in species number and planning conservation
strategy. New results support the ecological speciation model of
evolutionary divergence, indicating the importance of habitats in
biodiversity generation.
3. ON BROWNIAN MOTORS.
A great challenge for the field of nanotechnology is the design
and construction of microscopic motors that can use input energy
to drive directed motion in the face of inescapable thermal and
other noise. Driving such motion is what protein motors --
perfected over the course of millions of years by evolution -- do
in every cell in our bodies.
4. PHYSICAL CHEMISTRY: ON CHIRAL AMPHIPHILES.
Chiral amphiphiles represent excellent models for studying the
emergence of specific shapes at a macroscopic scale through
cooperative interactions between a large number of very small
building blocks, a topic of fundamental interest in chemistry,
biology, and materials science.
5. ON MALARIA IN AFRICA.
The current focus of malaria control programs in Africa is
rightly on the management of sick children through early
treatment with effective antimalarial drugs. However, this cannot
be the final strategy. The two first-line drugs, chloroquine and
sulfadoxine/pyrimethamine (Fansidar), are no longer effective in
many parts of East Africa where chloroquine resistance is
rampant.
6. ON GENOMIC MEDICINE.
Physicians began applying knowledge of genetics to human health
only at the start of the past century. For most of the 20th
century, many medical practitioners viewed genetics as an
esoteric academic specialty, but this is a view that is now
dangerously outdated.
7. ON PHASE TRANSFORMATIONS AND GRAIN NUCLEATION.
Grain nucleation and growth are important phenomena in
polycrystalline materials such as metals and most ceramics. New
measurements demonstrate that the activation energy for grain
nucleation is at least two orders of magnitude smaller than that
predicted by thermodynamic models.
8. ON SECURE COMMUNICATION USING QUANTUM ENTANGLEMENT.
The "ping-pong" protocol can be used for the transmission of
either a secret key or a plain text message. In the latter case,
the protocol is quasi-secure, i.e., an eavesdropper is able to
gain a small amount of message information before being detected.
In case of a key transmission, the protocol is asymptotically
secure.
9. ScienceWeek Notices and Subscription Information
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Section 2
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1. ON PROTEIN FOLDING DYNAMICS.
The term "villin" refers to calcium-regulated actin-binding
protein occurring in the microvilli of intestinal epithelial
cells and kidney proximal tubule cells. The molecule consists of
a large core fragment, the N-terminal portion, and a small
headpiece, the C-terminal portion. The headpiece strongly binds
F-actin.
C.D. Snow et al (Stanford University, US) discuss protein
folding, the authors making the following points:
1) Protein folding is difficult to simulate with classical
molecular dynamics. Secondary structure motifs such as alpha-
helices and beta-hairpins can form in 0.1 10 ęs (1), whereas
small proteins have been shown to fold completely in tens of
microseconds(2). The longest folding simulation to date is a
single 1-ęs simulation of the villin headpiece(3); however, such
single runs may miss many features of the folding process as it
is a heterogeneous reaction involving an ensemble of transition
states(4,5).
2) To establish a statistically favoured mechanism, map the free
energy surface, and to compare absolute rate and equilibrium
constants with experimental data requires multiple simulations of
any folding reaction. Such multiple sampling has only been
achieved for peptide systems. The prevailing view is that current
molecular dynamics cannot find the native state at the free
energy minimum owing to limitations of timescale and force field
accuracy. For example, performing a molecular dynamics simulation
for 10 ęs with a 2-fs time step on a simple system in implicit
solvent, such as our model protein BBA5, would require decades
for a typical modern CPU.
3) The authors report they have used a distributed computing
implementation to produce tens of thousands of 5 20-ns
trajectories (700 ęs) to simulate mutants of the designed mini-
protein BBA5. The fast relaxation dynamics these predict were
compared with the results of laser temperature-jump experiments,
and the computational predictions are in excellent agreement with
the experimentally determined mean folding times and equilibrium
constants. The rapid folding of BBA5 is due to the swift
formation of secondary structure. The authors suggest the
convergence of experimentally and computationally accessible
timescales will allow the comparison of absolute quantities
characterizing in vitro and in silico (computed) protein folding.
References (abridged):
1. Eaton, W. A., Mu¤oz, V., Thompson, P. A., Henry, E. R. &
Hofrichter, J. Kinetics and dynamics of loops, alpha-helices,
beta-hairpins, and fast-folding proteins. Acc. Chem. Res. 31,
745-753 (1998)
2. Mayor, U., Johnson, C. M., Daggett, V. & Fersht, A. R. Protein
folding and unfolding in microseconds to nanoseconds by
experiment and simulation. Proc. Natl Acad. Sci. USA 97, 13518-
13522 (2000)
3. Duan, Y. & Kollman, P. A. Pathways to a protein folding
intermediate observed in a 1-microsecond simulation in aqueous
solution. Science 282, 740-744 (1998)
4. Wolynes, P. G., Onuchic, J. N. & Thirumalai, D. Navigating the
folding routes. Science 267, 1619-1620 (1995)
5. Dill, K. A. & Chan, H. S. From Levinthal to pathways to
funnels. Nature Struct. Biol. 4, 10-19
Nature 2002 420:102
Related Background:
PROTEIN FOLDING: ENERGY LANDSCAPE THEORY
Jeffery G. Saven (University of Pennsylvania, US) discusses
protein folding. A predictive understanding of protein folding is
obscured by the complexity of proteins. The hallmark of protein
folding is the ability of an amino acid sequence to reversibly
acquire a well-defined and unique structure in a moderate amount
of time even though an extremely large number of structures are
possible. In the energy landscape approach to understanding
protein folding, the process is viewed as a collective and
cooperative phenomenon, with the focus of theory on the global
nature of the protein's free energy surface. Such a picture
emphasizes those general characteristics shared by proteins in a
structural class as well as those properties specific to
particular proteins. In such an approach, information about the
energetics of the unfolded as well as folded states must be
accounted for. This is an obvious consideration, since the
protein must effectively recognize and acquire one conformation
when a huge number of conformations are possible. Although much
has been learned about the energetics and features of unfolded
states from detailed atom-based simulations, such calculations
are computationally time-consuming. Given the apparent complexity
of the conformational free energy surface of a protein, the
energy landscape approach focuses on developing concepts that
simplify the description of the process. A prime goal of energy
landscape theory is to identify a handful of thermodynamic and
other simplifying parameters and variables that characterize
protein folding in both the folded state and in the ensemble of
partially folded conformational states.
J. Am. Chem. Soc. 2001 123:3113
Related Background:
ON EXPLANATIONS OF PROTEIN FOLDING
Since the 3-dimensional configuration of a protein is an
essential determinant of what the protein does in a biological
system, protein "folding", the process that leads to this
configuration, is a central focus in biophysical chemistry.
William A. Eaton (National Institutes of Health, US) presents a
review of current research in this field, the author making the
following points:
1) There are two aspects to the problem of protein folding. The
first is predicting the 3-dimensional structure of a protein from
its amino acid sequence; the second is to understand _how_
proteins fold. The problem of protein folding has recently
assumed additional importance as more and more human diseases
(e.g., Alzheimer's and Parkinson's diseases) are believed to be
caused by aggregation of misfolded proteins.
2) The question of _how_ a protein folds can be phrased more
precisely as follows: What are the sequences of structural
changes that occur in a polypeptide as it finds its way from the
myriad of possible structures in the *denatured state to the
final unique *native structure? How many different folding routes
exist, and what are their relative probabilities?
3) Until approximately a decade ago, the problem of understanding
how proteins fold was addressed by identifying and characterizing
one or two metastable structures believed to be obligatory
intermediates in a sequential process along a well-defined
protein-folding pathway. The prevailing view was that structural
characterization of such intermediates would give the clue to the
basic underlying mechanism, as in the study of organic chemical
reactions. However, unlike small-molecule chemical reactions, in
which covalent bonds are broken and new bonds formed in a
structurally well-defined transition state, the many degrees of
freedom of a polypeptide chain demand a different approach. A
polypeptide of 100 amino acids has a huge number of
conformations, even if only a tiny fraction of the more than
2^(100) (= 10^(30)) possible conformations are thermally
occupied. Understanding the complexities of protein folding at
the microscopic level, and developing models that make
quantitative predictions, therefore requires a statistical
approach, i.e., the theoretical and computational tools of
modern statistical mechanics.
4) Nonexponential kinetics have played an important role in
understanding conformational changes in native proteins. They are
particularly interesting for protein folding because they could
arise from a process that is "downhill" in free energy, i.e, one
in which the overall free energy barrier separating the native
from the denatured state is very small or nonexistent. For large
barriers, only the structures of the initial and final states are
observable, because structures along the folding route are too
sparsely populated. If, however, the barrier becomes very small
or disappears altogether, all of the structures can in principle
be detected and characterized by spectroscopy.
5) At the present time, there exists the exciting prospect of
performing single molecule experiments for direct exploration of
the energy landscape and folding routes. Finding proteins that
fold with a "downhill scenario" is an essential first step in
this quest. That some proteins will exhibit downhill folding,
moreover, is one of the novel theoretical predictions of an
energy landscape analysis of protein folding.
Proc. Nat. Acad. Sci. 1999 96:5897
Notes:
... ... *denatured state: In biochemistry, the term
"denaturation" refers to the complete unfolding and loss of
catalytic activity of a protein.
... ... *native structure: The "native" structure or
configuration of a biological macromolecule is the functional
state or configuration ordinarily assumed by the molecule in the
biological system in which the molecule occurs.
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2. ON HABITATS AND ECOLOGICAL SPECIATION.
R. Ogden and R.S. Thorpe (University of Wales, UK) discuss
ecological speciation, the authors making the following points:
1) Understanding speciation processes in rainforests is key to
predicting changes in species number and planning conservation
strategy (1). Ecological speciation due to divergent natural
selection has emerged as an alternative theory to speciation in
geographic isolation. Recent studies in support of an ecological
gradient model of speciation in rainforests have shown
morphological differences between habitats but have not tested
for a reduction in gene flow (2,3) or have not reported such a
reduction where it has been tested (3,4). Morphological variation
along ecological gradients may indicate diversification, but
speciation is not an inevitable consequence of population
differentiation (5), and molecular evidence of reduced gene flow
is needed to strengthen support for the theory of ecological
speciation.
2) The authors report a study in which molecular markers were
used to examine the effects of allopatric divergence and habitat
on levels of gene flow in the Caribbean lizard Anolis roquet.
Three study transects were constructed to compare variation in
microsatellite allele frequencies and morphology across
phylogenetic and habitat boundaries in northern Martinique.
Results showed reductions in gene flow to be concordant with
divergent selection for habitat type. No evidence could be found
for divergence in allopatry influencing current gene flow.
Morphological data match these findings, with multivariate
analysis showing correlation with habitat type but no grouping by
phylogenetic lineage. The results support the ecological
speciation model of evolutionary divergence, indicating the
importance of habitats in biodiversity generation.
References (abridged):
1. Moritz, C. , Patton, J. L. , Schneider, C. J. & Smith, T. B.
(2000) Annu. Rev. Ecol. Syst. 31, 533-563
2. Schneider, C. J. , Smith, T. B. , Larison, B. & Moritz, C.
(1999) Proc. Natl. Acad. Sci. USA 96, 13869-13873
3. Smith, T. B. , Schneider, C. J. & Holder, K. (2001) Genetica
112, 383-398
4. Smith, T. B. , Wayne, R. K. , Girman, D. J. & Bruford, M. W.
(1997) Science 276, 1855-1857
5. Magurran, A. E. (1998) Philos. Trans. R. Soc. London B 353,
275-286
Proc. Nat. Acad. Sci. 2002 99: 13612
Related Background:
ON TROPICAL SPECIES DIVERSITY
E. Bermingham and C. Dick (Smithsonian Institute, US) discuss
species diversity. Writing in 1878, the evolutionary biologist
Alfred Russel Wallace (1823-1913) suggested that the high species
diversity of the tropics could be accounted for by the greater
age of tropical environments -- providing more time for species
to accumulate -- compared with environments of temperate regions.
After all, parts of lowland South America have been draped in
tropical vegetation for over 100 million years, whereas the
distribution of temperate forests has tracked the push and pull
of glaciers. A century after Wallace, G.Ledyard Stebbins
introduced the "museum hypothesis", providing a name for the
more refined idea that "plant communities that have suffered the
least disturbance during the last 50 to 100 million years... have
preserved the highest proportion of archaic forms." This view of
Stebbins challenged the "cradle of diversity hypothesis" that had
largely supplanted Wallace's early notion of the importance of
time for explaining tropical species diversity. The cradle of
diversity hypothesis held that the tropics are a crucible of
evolution in which adaptive complexes arise owing to the biotic
complexity of tropical forests. The explosive radiation of New
World orchids, for example, is partly due to the group's
intricate coevolutionary interaction with pollinators. The idea
that high rates of tropical speciation, rather than age or
reduced rates of extinction, contribute to tropical forest
diversity gained added prominence with the publication of the
"refugia model" in the 1960s. This model posited that allopatric
divergence (i.e., divergence of very similar organisms that
cannot interbreed due to geographical isolation) in fragmented
ice-age forests acted as a species pump, supporting the
prediction that tropical species diversity is a recent event.
Thus, the question still remains: is most tropical diversity
ancient or new?
Science 2001 293:2214
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3. ON BROWNIAN MOTORS.
R.D. Astumian and P. Haenggi (University of Maine Orono, US)
discuss Brownian motors, the authors making the following points:
1) A great challenge for the burgeoning field of nanotechnology
is the design and construction of microscopic motors that can use
input energy to drive directed motion in the face of inescapable
thermal and other noise. Driving such motion is what protein
motors -- perfected over the course of millions of years by
evolution -- do in every cell in our bodies.(1)
2) To put the magnitude of the thermal noise in perspective,
consider that the chemical power available to a typical molecular
motor, which consumes approximately 100-1000 molecules of
adenosine triphosphate (ATP) per second, is 10^(-16) to 10^(-17)
W. In comparison, a molecular motor moving through water
exchanges about 4 x 10^(-21) J (the thermal energy kT at room
temperature) with its environment in a thermal relaxation time of
order 10^(-13) s. Thus, a thermal noise power of approximately
10^(-8) W continually washes back and forth over the molecule.
That power, which, according to the second law of thermodynamics
cannot be harnessed to perform work, is 8 to 9 orders of
magnitude greater than the power available to drive directed
motion. For molecules, moving in a straight line would seem to be
as difficult as walking in a hurricane is for us. Nonetheless,
molecular motors are able to move, and with almost deterministic
precision.
3) Inspired by the fascinating mechanism by which proteins move
in the face of thermal noise, many physicists are working to
understand molecular motors at a mesoscopic scale. An important
insight from this work is that in some cases thermal noise can
assist directed motion by providing a mechanism for overcoming
energy barriers. In those cases, one speaks of "Brownian
motors".(2)
References (abridged):
1. S. M. Block, Trends Cell Biol. 5, 169 (1995); J. Howard,
Nature 389, 561 (1997); R. D. Vale, R. D. Milligan, Science 288,
88 (2000).
2. P. Hanggi, R. Bartussek, in Nonlinear Physics of Complex
Systems: Current Status and Future Trends (Lecture Notes in
Physics, vol. 476), J. Parisi, S. C. Muller, W. Zimmerman, eds..
Springer-Verlag, New York, (1996), 294; F. Julicher, A. Ajdari,
J. Prost, Rev. Mod. Phys. 69, 1269 (1997); R. D. Astumian,
Science 276, 917 (1997). A comprehensive review is given by P.
Reimann, Phys. Rep. 361, 57 (2002). See also the articles in the
special issue on "Ratchets and Brownian Motors: Basics,
Experiments, and Applications," Appl. Phys. A 75 (August 2002).
Physics Today 2002 November
Related Background:
ON MYOSIN MOTOR PROTEINS
Fifty years ago, a biologist looking at a large living biological
cell through a light microscope could see motions on the surface
and in the interior of the cell, motions aplenty and all of it
mysterious. It was not until the 1960s that the microscale
structures involved in cell movements were roughly identified,
not until the 1970s that the biochemistry of these structures was
characterized, and not until the 1990s that a clearer picture of
the possible intricate movements of the "molecular motors" (motor
proteins) of living cells became apparent. An engineer viewing
some of the current models of biological molecular motors will
find nanoscale devices involving only a handful of
macromolecules, with each device engaged in a precise sequence of
repetitive movements --rotations, vibrations, translocations
along tracks, linear contractions, etc. -- the energy for these
motions derived from enzyme-catalyzed reactions, and all of these
devices assembled with apparent great precision by synthetic
processes controlled by information stored in the genome of the
cell. It is quite understandable if the engineer, for example,
while looking at a model of the macromolecular assembly evidently
responsible for the rotation of a flagellum, the whip-like
structure involved in bacterial movement, is flabbergasted. We
have apparently crossed a threshold into a world of nanoscale
"machinery" in biological cells, and cell biology in the 21st
century promises to be a source of extraordinary revelations.
It is now recognized that the interiors of biological cells are
structurally complex, and that this structure is dynamic.
Microtubules are part of the cytoskeleton of biological cells,
the quasi-rigid matrix that among other things determines cell
shape. The microtubules are 25 nanometers in diameter, and
composed of the protein tubulin. They occur in regular arrays in
various cell organelles, and in the cytoplasm in general, and
they contribute not only to cell shape, but also to cell
motility. Microfilaments are 4 to 6 nanometers in diameter,
highly variable in length, and are found in all eukaryotic cells.
They are composed of a protein called "actin" and several other
accessory proteins, and they are important in cell locomotion and
in the molecular dynamics of muscle cells. "Motor proteins" are
mechanico-chemical enzymes involved in locomotion or transport,
and there are three families of such proteins: kinesins, dyneins,
and myosins. Kinesins and dyneins are microtubule based motor
proteins, while myosin is a microfilament based motor protein. In
general, as mechanico-chemical enzymes, motor proteins convert
energy from hydrolysis of nucleotides to mechanical force, and
since they are involved in many important cellular events, the
molecular details are currently the focus of intensive research.
Myosin is a large protein with a molecular weight of
approximately 500K daltons, and it accounts for approximately
half the protein present in the myofibrils that comprise muscle
fibers. The myosin molecule consists of 6 polypeptide subunits: 2
heavy chains with a molecular weight of approximately 200K
daltons each and 4 light chains of approximately 20K daltons
each. In electron micrographs, purified myosin appears as a long
thin rod containing 2 globular heads protruding at one end. This
2-headed type of myosin is called "myosin-2" to distinguish it
from the smaller and single-headed myosin-1 molecule involved in
cytoplasmic movements in some non-muscle cells.
Michael A. Geeves (University of Kent, UK) discusses motor
proteins, the author making the following points:
1) Most organisms, whether they consist of a single cell or
billions, can move in a directed way, an ability that is largely
attributed to molecular motor proteins. Of these, myosin-2 is
perhaps the best understood because of its role in muscle
contraction. But other motors from the myosin family are also
required for processes involving motility, from cell division to
the transport of organelles within cells (1). One of the most
hotly debated issues (2) in this field centers on how myosins
move, and a theory known as the "lever-arm hypothesis" has
received much experimental support. This theory proposes that
tiny changes in myosin's "head" portion are amplified by the
adjoining "neck" (the lever arm) to produce large displacements
at the far end of the neck that translate into movement of the
whole protein (3), with the size of the displacement depending on
the length of the lever. Not everyone agrees, however, and the
theory has faced recent challenges.
2) Myosins consist of a head, a neck and a tail. The neck
comprises a structural element identified as an alpha-helix,
often attached to up to six polypeptide chains called light
chains. The tail is involved in connecting the motor to its
cargo, specifying the motor's cellular location and, in some
cases, allowing dimerization. (Myosins 2, 5 and 6, for example,
all consist of two identical proteins, each with its own head,
neck and tail.) The head attaches to and moves along tracks of
actin filaments. These are made up of globular monomers that
string together to form a chain; two chains twist round each
other to form a helical filament.
3) The breakdown of the cell's energy store, adenosine
triphosphate (ATP), powers myosin movement, driving large
structural changes that cause the myosin heads to cyclically
attach and detach from actin. Crystal structures of the myosin II
head show the neck emerging from it, stabilized by two light
chains, at an angle that varies by up to 60 degrees depending on
whether the head is bound to ATP or to the products of ATP
hydrolysis (adenosine diphosphate and phosphate). So the neck
looks like a lever, which led to the idea that it operates as a
rigid body to amplify small structural changes in the myosin
head, with longer necks leading to a larger displacement. Support
for this model comes from studies of myosins engineered to have
lever arms of different length. The results show a linear
relationship between the lever's length and the protein's speed
of moving actin filaments over a surface or step size in an
optical trap.
References (abridged):
1. Myosin Home Page: http://www.mrc-
lmb.cam.ac.uk/myosin/myosin.html
2. Cyranoski, D. Nature 408, 764-766 (2000).
3. Geeves, M. A. & Holmes, K. C. Annu. Rev. Biochem. 68, 687-728
(1999).
Nature 2002 415:129
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4. PHYSICAL CHEMISTRY: ON CHIRAL AMPHIPHILES.
In general, "amphiphiles" are molecules with parts (groups)
having diverse affinities for different solvents. For example,
polar groups have an affinity for water, while hydrocarbon groups
have an affinity for oils. Most detergents are amphiphiles,
molecules with a polar head and a long hydrocarbon tail. In this
context, however, possible solvent interactions are only one
aspect of amphiphilic character. The important consideration is
that amphiphiles tend to self-organize: groups of amphiphilic
molecules will form stable domains of polar interactions and
nonpolar interactions. For example, amphiphiles may form
"micelles", spherical or cylindrical arrangements with an
interior forming one interaction domain while the surface forms
another interaction domain. Larger aggregates may form vesicles
with diameters in the micron range. Since biological membranes
consist largely of amphiphile lipids, many researchers believe
prebiotic chemical systems may have involved amphiphile vesicles.
In chemistry, "chirality" is a property of certain asymmetric
molecules, the property being that the mirror images of the
molecules cannot be superimposed one on the other while facing in
the same direction.
D. Berthier et al (European Institute of Chemistry & Biology, FR)
discuss chiral amphiphiles, the authors making the following
points:
1) Chiral amphiphiles sometimes assemble into membrane structures
with twisted, helical, or cylindrical tubular morphologies that
express the chirality of their molecular constituents at a
supramolecular scale of micrometers.(1-5) In these mesoscopic
objects, the right or left sense of helicity depends directly on
the chirality of the amphiphile. However, the contribution "per
amphiphile" to the membrane chirality is very small. With the
average distance between the amphiphile headgroups being about
0.5-1 nm, thousands of headgroups can be aligned over one turn of
a helical membrane.
2) These objects represent excellent models for studying the
emergence of specific shapes at a macroscopic scale through
cooperative interactions between a large number of very small
building blocks, a topic of fundamental interest in biology. But
they also attract considerable interest for the applications that
they may have as templates for the helical crystallization of
macromolecules, in materials science, as templates for the growth
of inorganic replica, be they ceramics, silica, metals, or
semiconductors.
3) Several theories have been developed to relate the chiral
geometry of bilayer (or multilayer) membranes to the structures
of the amphiphilic components. Continuum theories invoke an
intrinsic chiral bending force within the bilayer originating
from the chiral packing of the molecules and/or from the chiral
symmetry breaking of the bilayer associated to a collective tilt
of the amphiphiles with respect to the bilayer normal. A model
using a discrete description of the molecules under the form of
chiral tetrahedrons has also been proposed, on the basis of an
effective pair potential to express the interaction between
adjacent chiral groups in a closed-packed lattice. In any case,
chiral bending relies on asymmetric interactions within the
membrane itself.
4) A simple examination of the chemical composition of chiral
membrane forming amphiphiles shows that they fulfill essential
requirements for the tight packing of the molecules. They may
contain very diverse functional groups, but they all have either
long alkyl chains or hydrogen bonding moieties, or both, which
enhance intermolecular interactions in bilayers. However, because
of the difficulty of assessing the structures of molecules within
a bilayer, detailed information about the conformations of these
amphiphiles and the asymmetric molecular interactions between
them have rarely been obtained.
References (abridged):
1. Yager, P.; Schoen, P. E. Mol. Cryst. Liq. Cryst. 1984, 106,
371-381.
2. Nakashima, N.; Asakuma, S.; Kim, J.-M.; Kunitake, T. Chem.
Lett. 1984, 1709-1712.
3. Yamada, K.; Ihara, H.; Ide, T.; Fukumoto, T.; Hirayama, C.
Chem. Lett. 1984, 1713-1716.
4. Fuhrhop, J.-H.; Schnieder, P.; Boekema, E.; Helfrich, W. J.
Am. Chem. Soc. 1988, 110, 2861-2867.
5. Yanagawa, H.; Ogawa, Y.; Furuta, H.; Tsuno, K. J. Am. Chem.
Soc. 1989, 111, 4567-4570.
J. Am. Chem. Soc. 2002 124:13486
Related Background:
SIMULATIONS OF PHOSPHOLIPID BILAYER FORMATION
S.J. Marrink et al (University of Groningen, NL) discuss
phospholipid bilayers. The self-aggregation of lipid molecules to
form bilayer membranes is a process fundamental to the
organization of life. Although qualitatively explained by the
hydrophobic effect, the molecular aggregation itself is a complex
phenomenon that has not been possible to study in detail
experimentally. The authors report a series of molecular dynamics
computer simulations that for the first time demonstrate the
possibility of observing the entire process at atomic resolution
with realistic lipids. Starting from random solutions, bilayers
are formed on time-scales of 10 to 100 nanoseconds, with
properties matching experimental data. Several key steps and
approximate time scales of the aggregation can be identified. The
final rate-limiting process is the reduction and disappearance of
large hydrophilic transmembrane water pores, which is of
biological relevance, e.g., for ion permeation. S.J. Singer and
G.L. Nicholson (1972) were the first to recognize the
implications of the extreme flexibility of membranes for the
structure of cellular walls, leading to the famous "fluid-mosaic
model" with diffusing lipids and proteins. However, the bilayer
formation process is extremely fast and involves subtle
rearrangements at the molecular level, making it elusive for
current experimental methods. The authors suggest their work
demonstrates the first simulations of aggregation of lipids into
bilayers with atomic resolution of the structure and
interactions.
J. Am. Chem. Soc. 2001 123:8638
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5. ON MALARIA IN AFRICA.
L. H. Miller and B. Greenwood (National Institutes of Health, US)
discuss malaria, the authors making the following points:
1) The current focus of malaria control programs in Africa is
rightly on the management of sick children through early
treatment with effective antimalarial drugs. However, this cannot
be the final strategy. The two first-line drugs, chloroquine and
sulfadoxine/pyrimethamine (Fansidar), are no longer effective in
many parts of East Africa where chloroquine resistance
(introduced from Asia) is rampant. Combinations of new drugs may
help to slow the emergence and spread of resistant parasites (1),
but control strategies based on early treatment mean a never-
ending struggle to develop and deploy new drugs before the
Plasmodium malaria parasites become resistant to existing drugs.
Thus, the long-term control strategy must be to interrupt the
transmission of this parasite. Unfortunately, this will be
extremely difficult in parts of Africa where people may be bitten
as many as 1000 times a year by infected mosquitoes. Insecticide-
treated bed nets -- now being vigorously promoted in many parts
of Africa -- reduce bites from infected mosquitoes by as much as
90% (2). However, their effectiveness is already under threat as
a result of the emergence of pyrethroid resistance in Anopheles
funestus in Mozambique and in A. gambiae in agricultural areas of
West Africa (3). Household spraying with residual insecticides is
highly effective in reducing malaria in some parts of Africa, but
it is logistically demanding, costly, and may have adverse
environmental effects.
2) There are many ways to reduce malaria transmission, but none
can provide a complete block in transmission, particularly in the
highly endemic areas of Africa (4), and new approaches are
desperately needed (5). Publication of the Plasmodium falciparum
and Anopheles gambiae genomes represents a big step forward in
our search for new tools for controlling malaria. Combined
deployment of three strategies that each have the potential to
reduce malaria transmission by 90% -- drug treatment,
vaccination, and vector control -- should be sufficient to stop
transmission, even in highly endemic areas of Africa. We will
need to first test such strategies in areas with a low intensity
of transmission before attempting the challenging task of
preventing malaria transmission in the highly endemic areas of
Africa.
References (abridged):
1. N. J. White, Drug Resist. Updates 1, 3 (1998).
2. S. W. Lindsay, et al., Med. Vet. Entomol. 3, 263 (1989).
3. F. Chandre, et al., Bull. WHO 77, 230 (1999).
4. L. Molineaux, G. Gramiccia, The Garki Project (World Health
Organization, Geneva, Switzerland, 1980).
5. B. Greenwood and T. Mutabingwa, Nature 415, 670 (2002).
Science 2002 298:121
Related Background:
IN VITRO DEVELOPMENT OF MALARIA MOSQUITO
The disease malaria is caused by a type of protozoan with the
general name Plasmodium, an organism characterized by a sequence
of life cycles involving different organismic forms. The asexual
cycle occurs in the liver and red blood cells of vertebrates
(including humans), and the sexual cycle occurs in mosquitoes.
Essentially, the asexual form is ingested by blood-sucking
mosquitoes, and in the mosquito the asexual form is induced to
produce the sexual form necessary to complete the total life
cycle. The details of the process are as follows: Plasmodium
cells called "gametocytes" (precursors of gametes) in human blood
are ingested by the mosquito, and in the mosquito, apparently
within seconds, gametocytes are induced into "gametogenesis",
producing gametes. These gametes produce a cell-type called
"sporozoites", which accumulate in the salivary gland of the
mosquito, from where they are injected into the vertebrate blood
stream when the mosquito feeds on vertebrate blood. The
sporozoites accumulate in the vertebrate liver, where they
multiply and produce a form (merozoites) that invades red blood
cells, replicates, destroys red blood cells, and so on, with an
eventual decline in this asexual replication. However, after
invasion of red blood cells, some merozoites produce gametocytes,
which have the genomic potential for restarting the total life
cycle. These gametocytes cannot self-replicate, and they die
unless ingested by a mosquito, but once in the mosquito, the
total life cycle begins again. There are apparently 2 inducers of
gametogenesis in vivo (i.e., in the mosquito): one inducer is a
pH of 7.5 to 7.6, and the other inducer has been thought to be an
unknown mosquito-derived gametocyte-activating factor.
E.M. Al-Olayan et al (Keele University, UK) discuss the complete
development of the malaria parasite in vitro, the authors making
the following points:
1) For over a century, a major objective of malaria control
programs has been to block parasite transmission by mosquitoes.
Such approaches would clearly benefit from a better understanding
of parasite development within the vector, initiated when
gametocytes are taken up in a blood meal. Fertilization of
macrogametes within the mosquito midgut produces zygotes that
transform into motile and invasive ookinetes. These penetrate and
traverse the midgut epithelium and become sessile vegetative
oocysts lying beneath the midgut basement lamina, each
potentially producing 2 to 8000 sporozoites. Knowledge of the
mosquito-related factors regulating these processes is improving,
but it is difficult to determine the specific and separate
effects of these factors in vivo. Early events associated with
midgut invasion have recently been studied in vitro with the use
of midgut preparations or co-cultured mosquito cells, but these
systems do not sustain long-term development or simulate oocyst
interaction with the basal lamina and do not permit investigation
of sporozoite differentiation.
2) Fertilization and ookinete development can be achieved in
vitro for many malaria parasite species, including Plasmodium
berghei, a parasite of rodents. These culture systems have
facilitated the study of ookinete molecules that may be targeted
by antibodies induced by transmission-blocking vaccines or drugs.
After many pioneering attempts, it is only recently that in vitro
transformation of Plasmodium gallinaceum and Plasmodium
falciparum ookinetes into oocysts and sporozoites has been
achieved, but the numbers of oocysts produced are low and, more
importantly, the infectivity of these sporozoites has not been
demonstrated.
3) The authors report they have cultured gametocytes of
Plasmodium berghei through to infectious sporozoites with
efficiencies similar to those recorded in vivo and without the
need for salivary gland invasion. Oocysts developed
extracellularly in a system whose essential elements include co-
cultured Drosophila S2 cells, basement membrane matrix, and
insect tissue culture medium. Sporozoite production required the
presence of para-aminobenzoic acid. Thus the entire life cycle of
P. berghei, a useful model malaria parasite, can now be achieved
in vitro, and the authors suggest this immediately opens up
important new areas of investigation.
References (abridged):
1. P. F. Billingsley and R. E. Sinden, Parasitol. Today 13:297
(1997).
2. A. Ghosh, M. J. Edwards, M. Jacobs-Lorena, Parasitol. Today
16:196 (2000)
3. R. E Sinden and P. F. Billingsley, Trends Parasitol. 17:209
(2001).
4. M. Shahabuddin and P. F. Pimenta, Proc. Nat. Acad. Sci.
95:3385 (1998).
5. H. Zieler and J. A. Dvorak, Proc. Nat. Acad. Sci. 97:11516
2000).
Science 2002 295:677
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6. ON GENOMIC MEDICINE.
A.E. Guttmacher and F.S. Collins (National Institutes of Health,
US) discuss genomic medicine, the authors making the following
points:
1) Humans have known for millennia that heredity affects
health.(1) However, the seminal contribution of Gregor Mendel
(1822-1884) to the elucidation of the mechanisms by which
heredity affects phenotype occurred less than 150 years ago, and
physicians began applying this knowledge to human health only at
the start of the past century. For most of the 20th century, many
medical practitioners viewed genetics as an esoteric academic
specialty, a view that is now dangerously outdated.
2) The recent completion of the draft sequence of the human
genome(2,3) and related developments have increased interest in
genetics, but confusion remains among health professionals and
the public about the role of genetic information in medical
practice. Inaccurate beliefs about genetics persist, including
the view that in the past it had no effect on the practice of
medicine and that its influence today is pervasive. In fact, for
decades knowledge of genetics has had a large role in the health
care of a few patients and a small role in the health care of
many. We have recently entered a transition period in which
specific genetic knowledge is becoming critical to the delivery
of effective health care for everyone.
3) If genetics has been misunderstood, genomics is even more
mysterious -- what, exactly, is the difference? Genetics is the
study of single genes and their effects. "Genomics"(4), a term
coined only 15 years ago, is the study not just of single genes,
but of the functions and interactions of all the genes in the
genome. Genomics has a broader and more ambitious reach than does
genetics. The science of genomics rests on direct experimental
access to the entire genome and applies to common conditions,
such as breast cancer(5) and colorectal cancer, human
immunodeficiency virus (HIV) infection, tuberculosis, Parkinson's
disease, and Alzheimer's disease. These common disorders are also
all due to the interactions of multiple genes and environmental
factors. They are thus known as multifactorial disorders. Genetic
variations in these disorders may have a protective or a
pathologic role in the expression of diseases.
References (abridged):
1. Adams FL. The genuine works of Hippocrates. Vol. 2. New York:
William Wood, 1886:338.
2. Lander ES, Linton LM, Birren B, et al. Initial sequencing and
analysis of the human genome. Nature 2001;409:860-921. [Erratum,
Nature 2001;411:720, 412:565.
3. Venter JC, Adams MD, Myers EW, et al. The sequence of the
human genome. Science 2001;291:1304-1351. [Erratum, Science
2001;292:1838.
4. McKusick VA, Ruddle FH. A new discipline, a new name, a new
journal. Genomics 1987;1:1-2.
5. Armstrong K, Eisen A, Weber B. Assessing the risk of breast
cancer. N Engl J Med 2000;342:564-571.
New Engl. J. Med. 2002 347:1512
Related Background:
DEFINING DISEASES IN THE GENOMICS ERA
L.K.F. Temple et al (University of Toronto, CA) discuss concepts
of disease in the genomics era. The human genome sequence will
dramatically alter how we define, prevent, and treat disease. As
more and more genetic variations among individuals are
discovered, there will be a rush to label many of these
variations as disease-associated. The authors suggest we need to
define the term "disease" so that it incorporates our expanding
genetic knowledge, taking into account the possible risks and
adverse consequences associated with certain genetic variations,
while acknowledging that a definition of disease cannot be based
solely on one genetic abnormality. The authors point out that the
human genetic sequence is likely to reveal many harmless genetic
variations that will turn out not to be
associated with disease. Disease is a fluid concept influenced by
societal and cultural attitudes that change with time and in
response to new scientific and medical discoveries. Until we
resolve questions about polymorphisms, incomplete penetrance of
genetic mutations, and the contribution of environmental factors
to disease etiology, we will not be able to assess the
probability of adverse consequences associated with a particular
gene abnormality. Until a mutation is demonstrated to involve a
defined risk of developing adverse consequences, individuals
carrying that mutation should not be considered diseased.
Science 2001 293:807
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7. ON PHASE TRANSFORMATIONS AND GRAIN NUCLEATION.
S.E. Offerman et al (Delft University of Technology, NL) discuss
grain nucleation, the authors making the following points:
1) Grain nucleation and growth are important phenomena in
polycrystalline materials such as metals and most ceramics. They
govern the kinetics of many phase transformations and
recrystallization processes that take place during processing.
The final average grain size after the transformation is directly
related to the strength of the material. In general, a smaller
average grain size results in a stronger material. Despite the
various transformation models that have been proposed in the past
60 years, the kinetics of these phase transformations is still
poorly understood. Most of these models are based on the
classical nucleation theory(1) and the law of parabolic grain
growth as derived by Zener (2), which describe the behavior of
individual grains in the bulk of the material.
2) The experimental techniques that have been available to verify
these nucleation and growth models are limited to either
observations at the surface or the determination of the average
grain growth behavior in the bulk (3). The development of x-ray
microscopes at synchrotron sources with focused high-energy x-
rays has created the opportunity to study individual grains in
the bulk of a material (4,5). In addition, these measurements
give unique information about the grain nucleation during the
phase transformation. Because of a combination of fundamental
scientific interest and technological importance, the phase
transformations in steel have been investigated more extensively
than those in any other material.
3) The authors report measurements that demonstrate that the
activation energy for grain nucleation is at least two orders of
magnitude smaller than that predicted by thermodynamic models.
The observed growth curves of the newly formed grains confirm the
parabolic growth model but also show three fundamentally
different types of growth. Insight into the grain nucleation and
growth mechanisms during phase transformations contributes to the
development of materials with optimal mechanical properties.
References (abridged):
1. J. W. Christian, The Theory of Transformations in Metals and
Alloys (Pergamon, Oxford, 1981).
2. C. Zener, J. Appl. Phys. 20, 950 (1949).
3. C. E. Krill III, et al., Phys. Rev. Lett. 86, 842 (2001).
4. E. M. Lauridsen, D. J. Jensen, H. F. Poulsen, U. Lienert,
Scripta Mater. 43, 561 (2000).
5. L. Margulies, G. Winther, H. F. Poulsen, Science 292, 2392
(2001).
Science 2002 298:1003
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8. ON SECURE COMMUNICATION USING QUANTUM ENTANGLEMENT.
K. Bostroem and T. Felbinger (University of Potsdam, DE) discuss
quantum entanglement, the authors making the following points:
1) Cryptographic schemes based on quantum mechanics are usually
nondeterministic [1-3]. Alice, the sender, can encode a classical
bit into a quantum state, which is then sent to Bob, but she
cannot determine the bit value that Bob will finally decode. In
spite of that, such nondeterministic communication can be used to
establish a shared secret key between Alice and Bob, consisting
of a sequence of random bits. This secret key can then be used to
encrypt a message which is sent through a classical public
channel. Recently, a novel quantum communication protocol has
been presented [4] that allows secure direct communication, where
the message is deterministically sent through the quantum
channel, but can be decoded only after a final transmission of
classical information.
2) The authors present a communication scheme, the "ping-pong
protocol", that also allows for deterministic communication. This
protocol can be used for the transmission of either a secret key
or a plain text message. In the latter case, the protocol is
quasi-secure, i.e., an eavesdropper is able to gain a small
amount of message information before being detected. In case of a
key transmission, the protocol is asymptotically secure. In
contrast to other quantum cryptographic schemes, the presented
scheme is instantaneous; i.e., the information can be decoded
during the transmission and no final transmission of additional
information is needed. The basic idea of the protocol, encoding
information by local operations on an EPR pair, has already been
raised by Bennett and Wiesner [5]. In the present protocol, the
authors follow this idea, but abandon the dense coding feature
in favor of a secure transmission.
3) In summary: A novel secure communication protocol is
presented, based on an entangled pair of qubits and allowing
asymptotically secure key distribution and quasi-secure direct
communication. Since the information is transferred in a
deterministic manner, no qubits have to be discarded. The
transmission of information is instantaneous, i.e., the
information can be decoded during the transmission. The security
against arbitrary eavesdropping attacks is provided. In case of
eavesdropping attacks with full information gain, the detection
rate is 50% per control transmission. The experimental
realization of the protocol is feasible with relatively small
effort, which also makes commercial applications conceivable.
References (abridged):
1. C. H. Bennett and G. Brassard, Proceedings of the IEEE
International Conference on Computers, Systems, and Signal
Processing, Bangalore (IEEE, New York, 1984), pp. 175-179.
2. A. Ekert, Phys. Rev. Lett 67, 661 (1991).
3. D. Bruss, Phys. Rev. Lett. 81, 3018 (1998).
4. A. Beige, B.-G. Englert, C. Kurtsiefer, and H. Weinfurter,
Acta Phys. Pol. A 101, 357 (2002).
5. C. Bennett and S. J. Wiesner, Phys. Rev. Lett 69, 2881 (1992).
Phys. Rev. Lett. 2002 89:187902
Related Background:
QUANTUM CRYPTOGRAPHY: ON PRIVATE QUANTUM ENTANGLEMENT OVER
ARBITRARY DISTANCES
Quantum mechanical entanglement is a phenomenon that has caught
the imagination of the public as one of the more bizarre
consequences of fundamental physical theory. Entanglement is
unique to quantum mechanics, and involves a relationship (a
"superposition of states") between the possible quantum states of
two entities such that when the possible states of one entity
collapse to a single state as a result of suddenly imposed
boundary conditions, a similar and related collapse occurs in the
possible states of the entangled entity no matter where or how
far away the entangled entity is located. Entanglement arises
from the wave function equation of quantum mechanics, which has
an array of possible function solutions rather than a single
function solution, with each possible solution describing a set
of possible probabilistic quantum states of the physical system
under consideration. Upon fixation of the appropriate boundary
conditions, the array of possible solutions collapses into a
single solution. For many quantum mechanical physical systems,
the fixation of boundary conditions is a theoretical and
fundamental consequence of some interaction of the physical
system with something outside that system, e.g., an interaction
with the measuring device of an observer. In this context, two
entities that are described by the same array of possible
solutions to the wave function equation are said to be
"coherent", and when events decouple these entities, the
consequence is said to be "decoherence". As a physical
phenomenon, entanglement was discussed many years ago, most
particularly following the publication in 1935 of the often
quoted Einstein-Podolsky-Rosen paper (the "EPR paper") (Phys.
Rev. 1935 47:777). These discussions have been in the form of
"gedanken" (thought) experiments involving two quantum-mechanical
entangled entities. More recently, however, there have been
laboratory constructions of actual quantum mechanical systems
exhibiting such entanglement phenomena, and the reportage of
these laboratory arrangements by the media have engaged the
public fancy. Essential here is that any purely verbal account of
quantum mechanical phenomena is severely limited by the
constraint that the properties of quantum mechanical systems can
be precisely described only by the equations relevant for those
systems, and all other descriptions
usually introduce serious ambiguities. In any case, an "EPR pair"
is a pair of entangled quantum entities.
H. Aschauer and H.J. Briegel (Ludwig-Maximilians University, DE)
discuss private quantum entanglement, the authors making the
following points:
1) Quantum cryptography promises the security of data
transmission against any eavesdropping attack allowed by the laws
of physics. The first quantum cryptography protocol was described
by Bennett and Brassard as early as 1984 [1]. Later, in 1991,
Ekert presented a scheme based on Bell's theorem [2]. Though the
security of these protocols is easy to prove under ideal
conditions, much work has been spent to prove the security under
realistic circumstances.
2) In all quantum cryptography protocols, a possible eavesdropper
is identified because of the disturbance that he or she
introduces when trying to gain information about a quantum state
that is transmitted. The problem is that every quantum channel
introduces innocuous noise itself, which cannot, in principle, be
distinguished from noise introduced by an eavesdropper. For that
reason, a proof of unconditional security of quantum cryptography
has to assume that all noise in the channel is due to the
interference of an eavesdropper.
3) Two different techniques have been developed to deal with
these difficulties: Classical privacy amplification allows the
eavesdropper to have partial knowledge about the raw key built up
between the communicating parties Alice and Bob. From the raw
key, a shorter key is "distilled", about which Eve has vanishing
(i.e., exponentially small in some chosen security parameter)
knowledge. Despite the simple idea, proofs taking into account
all eavesdropping attacks allowed by the laws of quantum
mechanics have been shown to be technically involved [3-5].
Recently, Shor and Preskill [2000] have given a simpler physical
proof relating the ideas in [3,4] to quantum error correcting
codes. Quantum privacy amplification, on the other hand, employs
an entanglement purification protocol that eliminates any
entanglement with an eavesdropper by creating a few perfect EPR
pairs out of many imperfect (or impure) EPR pairs. In principle,
this method guarantees security against any eavesdropping attack.
However, the problem is that the quantum privacy amplification
protocol assumes ideal quantum operations. In reality, these
operations are themselves subject to noise.
4) The authors report a security proof of quantum cryptography
based entirely on entanglement purification. Their proof applies
to all possible attacks (individual and coherent), and implies
the security of cryptographic keys distributed with the help of
entanglement-based quantum repeaters. The authors prove the
security of the obtained quantum channel, which may be used not
only for quantum key distribution, but also for secure, albeit
noisy, transmission of quantum information.
References (abridged):
1. C. H. Bennett and G. Brassard, in Proceedings of IEEE
International Conference on Computers, Systems and Signal
Processing, Bangalore, India (IEEE, New York, 1985), pp. 175-179.
2. A. Ekert, Phys. Rev. Lett. 67, 661 (1991).
3. D. Mayors, in Advances in Cryptology-Proceedings of Crypto '96
(Springer-Verlag, New York, 1996), pp. 343-357; see also quant-
ph/9802025.
4. E. Biham et al., in Proceedings of the Thirty-Second Annual
ACM Symposium on Theory of Computing (ACM Press, New York, 2000),
pp. 715-724.
5. H. Inamori, quant-ph/0008064.
Phys. Rev. Lett. 2002 88:147902
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