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"Membrane
Proteins: Experimental and Computational Approaches to
Understanding Cellular Function"
May 4-5, 2002
Center for Biophysics & Computational
Biology
University of Illinois, Urbana-Champaign
Organizers:
Colin Wraight, Tony Crofts, Zan Luthey-Schulten, and John Whitmarsh
Sponsorship: Olga G. Nalbandov
Lecture Fund, Center for Biophysics & Computational Biology, School
of Molecular & Cell Biology, Department of Molecular & Integrative
Physiology, Molecular Biophysics Training Grant, Theoretical Biology
Group, Department of Biochemistry, School of Chemical Sciences, Department
of Physics.
Membrane proteins
are responsible for many of the most important and most striking characteristics
of life, including energy production, sensory perception, ion transport
and bioelectricity, cell adhesion and movement, cell recognition and
signaling. From the current genomics data base, at least 1/3 of all
proteins are expected to be membrane-associated. However, very few
membrane proteins have been structurally characterized at the resolution
necessary to contribute to an understanding of function - the structures
of approximately 10,000 globular proteins have been determined (mostly
by X-ray crystallography), but only about a dozen distinct membrane
proteins have been so defined, at this time. This is about to change.
The X-ray crystal structure of the first membrane protein was published
in 1985. For the determination of the three-dimensional structure
of the photosynthetic reaction center, Hartmut Michel , Johan Deisenhofer
and Robert Huber received the Nobel prize just three years later,
in 1988. This fundamental achievement motivated intense efforts
on other major membrane proteins with notable success with some
other bioenergetic components and the light harvesting components
of bacterial and plant photosynthesis. In the 10 years after the
first reaction center structure, two more membrane proteins were
structurally resolved in this way, but since 1995 a dramatic acceleration
has been seen, resulting from a new understanding of the principles
behind crystallization of membrane proteins. These include genuine
behemoths, such as the mammalian cytochrome c oxidase and the H+
pumping ATPase enzyme, extraordinarily high resolution structures
of the ion-pumping photoenzyme bacteriorhodopsin, as well as the
first ion-conducting channel proteins, so long awaited by electrophysiologists.
The atomic resolution of these structures has had a profound impact
on the scientific community. The photosynthetic reaction center
structure galvanized a whole generation of physicists and physico-chemists
to enter the field to understand, in microscopic quantum detail,
how this remarkable protein directs energy-storing electron transfer
with a quantum yield of almost 100%, with photochemical events occuring
in time domains from picoseconds to seconds. The bacteriorhodopsin
structure has recently given us the first detailed mechanism of
protein conformational dynamics that drive ion pumping, as well
as first principle applications of sophisticated quantum chemical
calculations to excited state dynamics in a biological system. The
cytochrome oxidase structure has driven experimental investigations
to close in on the mechanism of H+ ion pumping in respiration, the
major energy releasing process of the biosphere. The ATPase structure
immediately evokes a unique rotary operation of this remarkable
molecular motor and reveals essential details of the mechanism that
are also applicable to other mechano-enzymes. And the first structure
of a potassium conducting ion channel protein has unleashed a torrent
of creative understanding of this universal activity of biological
membranes, and its essential properties of ion selectivity and gating.
As an indication of the accelerating pace of discovery in this major
frontier of biological function, 8 novel structures of membrane
proteins have been published in the last 2 years, compared to no
more than 5 in the previous 12 years. In some cases, sufficient
information on functionally related systems has been acquired that
we are now poised to put the parts together and understand their
function as an integrated system. This is especially true of the
energy conserving systems of respiration and photosynthesis. In
the latter case, not only are the structures of the active enzymes
known - the reaction center, the cytochrome bc1 complex and the
ATPase, plus soluble cytochrome c2, which links the the reaction
center and bc1 complex - but also the remarkable "wheel-like"
structures of the light harvesting pigment-proteins, which surround
the reaction center and funnel excitation energy to it on the picosecond
time scale. The integrated function of such supramolecular assemblies
is now emerging as the next challenge in computational biology.
The membrane systems now emerging in structural detail have been
so long awaited and have been so well studied at the phenomenological
level, that they are immediately ripe for sophisticated mechanistic
interpretation and computational study. Furthermore, bioinformatic
analysis of large scale genome projects, and mutagenesis studies
of related protein sequences, are revealing key functional sites
in dozens of homologous membrane proteins. This has created an extensive
knowledge base of sequences and partial structures, with assigned
functions, for which mechanistic details can be explored by computational
modeling. The synergy between experiment and computation is now
at a premium in the related areas of functional description of membrane
proteins and functional integration into coordinated membrane activity.
Comparative genomics studies that have only just become possible,
now give us an idea how many of these membrane proteins are integrated
into the overall functional architecture of an organism. Indeed,
a recent analysis has demonstrated the existence of a minimal set
of such functions necessary to maintain the cell of a parasitic
organism.
The symposium is intended to bring together ideas from experimental,
computational and structural biology and bioinformatics, relevant
to understanding diverse cell membrane functions, including the
fundamental processes of energy production, cell signaling and the
transport of ions and nutrients into cells.
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