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  • Gina Miller
    And then says: From: Science-Week ... A Weekly Email Digest of the News of Science A journal
    Message 1 of 1 , Aug 3, 1999
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      And then <eugene.leitl@...-muenchen.de> says:
      From: "Science-Week" <prismx@...>
      -------------- Enclosure number 1 ----------------SCIENCE-WEEK
      A Weekly Email Digest of the News of Science
      A journal devoted to the improvement of communication
      between the scientific disciplines, and between scientists,
      science educators, and science policy makers.August 6, 1999 -- Vol. 3 Number
      32
      -----------------------------------------------
      Books must follow sciences, and not sciences books.-- Francis Bacon
      (1561-1626)
      -----------------------------------------------Contents of This Issue:
      1. On Aesthetics as a Guide to Theory2. Large-Scale Structures in the
      Universe
      3. Protein Folding: On Oleg Ptitsyn4. Structural Mechanisms of Endocytosis
      5. Immunology: T-Cell Synapses6. On DNA Vaccines
      In Focus: On the Genetic Code vs. Human Language
      -----------------------------------------------------------
      1. ON AESTHETICS AS A GUIDE TO THEORY2. LARGE-SCALE STRUCTURES IN THE
      UNIVERSE
      3. PROTEIN FOLDING: ON OLEG PTITSYN (1929-1999)
      Proteins are polymers consisting of long chains of amino acid
      residues, but that is only the beginning of their functional
      chemistry. In biological systems, proteins assume various complex
      high-order configurations ("folding"), and it is these
      configurations that usually determine the roles of proteins as
      biochemical entities in the biological system. An important goal
      of molecular biology is to understand the structural and
      functional features of proteins, in particular the mechanisms
      responsible for specific protein folding. In recent decades, one
      of the leading personalities in the field of protein folding was
      Oleg Ptitsyn (1929-1999). For nearly 30 years, Ptitsyn advocated
      the concept of the "molten globule" as a key intermediate in
      protein folding. Ptitsyn's fundamental idea that proteins can
      adopt compact structures without the close-packed side-chain
      interactions characteristic of *native proteins is now implicit
      in virtually every discussion of the subject.
      ... ... C.M. Dobson and R.J. Ellis (2 installations, UK) present
      a biographical essay on Oleg Ptitsyn, the authors making thefollowing
      points:
      1) Ptitsyn was born in Leningrad in 1929, and he received a
      doctorate in physics from the University of Leningrad at the age
      of 25. His early work was on the physics of polymers at the
      Institute of High Molecular Weight Compounds in Leningrad, but he
      soon became interested in proteins and began work on protein
      folding. With others, Ptitsyn founded the Institute of Protein
      Research in Pushchino, a town approximately 70 miles from Moscow.
      2) In the early 1970s, Ptitsyn speculated that the protein-
      folding problem might be made much simpler if a polypeptide chain
      folds first into a flexible state with the usual positioning of
      *helices and sheets, but without the intricate and detailed
      packing of the various side chains found in a fully native
      protein. There was no experimental evidence for this proposal at
      that time, but soon such evidence began to emerge from studies of
      *protein denaturation in various laboratories.
      3) Ptitsyn introduced the strategy of a combination of
      physical methods to search for this new state of proteins. The
      name "molten globule" was first used by Akiyoshi Wada in Japan.
      The Ptitsyn laboratory subsequently made the major advance of
      identifying species in kinetic experiments that fitted Ptitsyn's
      definition of a molten globule, and then relating this state to
      the mechanism of the folding process itself.
      4) Concerning Ptitsyn the person, the authors write: "Oleg
      Ptitsyn was a gentle, kindly person, whose diminutive and
      bustling figure was familiar around the conference and lecture
      halls of the world... He died on 22 March, just before he was due
      to give a lecture at the University of Warwick, during one of his
      frequent trips to Britain. It was as he would have wished. He
      died, as he had lived, earnestly engaged in the practice of
      science, and looking forward to intense discussions about hislatest ideas."
      -----------C.M. Dobson and R.J. Ellis: Oleg Ptitsyn (1929-1999).
      (Nature 8 Jul 99 400:122)QY: Christopher M. Dobson
      [chris.dobson@...]
      -----------Text Notes:
      ... ... *native proteins: The "native" state 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.
      ... ... *helices and sheets: The "primary structure" of a
      polypeptide chain is the actual sequence of amino acid residues;
      the "secondary structure" is a low-order folding of the chain;
      the "tertiary structure" is a high-order folding of the molecule.
      Concerning the secondary structure, there are two main types: the
      alpha configuration is a spiral configuration in which successive
      turns of the helix are held together by hydrogen bonds; the beta
      configuration is a configuration in which the chain is almost
      fully extended and hydrogen bonded to an adjacent polypeptide
      chain, with successive chains often involved to form "sheets".
      ... ... *protein denaturation: Usually irreversible complete
      protein unfolding (without rupture of peptide bonds) and loss of
      catalytic activity if the protein is an enzyme.-------------------
      Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 6Aug99
      -------------------Related Background:ON THE CHEMICAL PHYSICS OF PROTEIN
      FOLDING
      ... ... C.L. Brooks et al present a short review of protein
      folding from the perspective of chemical physics, and with a
      focus on the work of their own group, the authors make the
      following points: 1) The question of the mechanism of protein
      folding was once thought to be entirely analogous to the question
      of mechanism in intermediary metabolism or classical organic
      chemistry: the essential classical idea was that a protein
      folding pathway involves a series of discrete intermediates. Such
      discrete intermediates do occur in the late stages of protein
      folding, but to answer the practical questions of structure
      prediction and design, a new viewpoint on folding is required. 2)
      The authors suggest this new viewpoint is that of chemical
      physics rather than that of classical chemistry, and that the
      chemical physics view requires a new set of theoretical ideas,
      computational techniques, and major advances in experimental
      methodology. 3) The authors suggest the theoretical framework for
      the new chemical physics approach to protein folding should be
      that of "*energy landscape theory", which asserts that "a full
      understanding of the folding process requires a global overview
      of the energy landscape." 4) The authors propose that the protein
      folding energy landscape resembles a partially rough funnel
      riddled with energy traps where the protein can transiently
      reside. There is no unique pathway but a multiplicity of
      convergent folding routes toward the native state... The authors
      state that the essence of the funnel energy landscape idea is
      competition between the tendency toward the folded state and
      trapping because of "ruggedness" of the funnel. 5) Concerning
      theoretical modeling, the authors point out that simulations with
      detailed atomic models are extremely intensive numerically, so
      that the number and size of systems that can be studied is
      limited. Simulation models of intermediate complexity have
      therefore been used. 6) Concerning experimental approaches to
      exploring the energy landscape of protein folding, there are
      various new methods involving the physical monitoring of folding
      from an unfolded state, for example, monitoring in the
      microsecond range following initiation of folding by a
      nanosecond-scale step-change in ambient temperature. The authors
      conclude: "Experiments are beginning to build up a *phase diagram
      of folding kinetics that can be used to test and refinetheoretical models."
      -----------C.L. Brooks et al (4 authors at 3 installations, US)
      Chemical physics of protein folding.
      (Proc. Natl. Acad. Sci. US 15 Sep 98 95:11037)
      QY: Charles L. Brooks, Scripps Research Institute 619-784-1000.-----------
      Text Notes:... ... *energy landscape: The "energy landscape" here refers to
      the contours of what is essentially a classical energy/entropy
      diagram, with the native configuration state positioned at the
      bottom of a deep potential well, in this case a funnel with sides
      containing miniature energy wells or "traps".
      ... ... *phase diagram: A classical graphical representation of
      the equilibrium relationships between phases of a chemicalsystem.
      -------------------
      Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 23Oct98
      -------------------Related Background:
      ON THE THERMODYNAMIC HYPOTHESIS OF PROTEIN FOLDING
      Proteins are macromolecules that assume specific high-order
      configurations, with each type of protein molecule folding into
      the specific configuration necessary for its function. There are
      two central aspects of this folding: it occurs extremely rapidly,
      on the order of milliseconds to minutes after first synthesis of
      the polymer, and the final configuration achieved is always
      identical for each type of protein. Thus, protein A rapidly folds
      into the protein A-conformation, and protein B rapidly folds into
      the protein B-conformation. The question is how does this happen?
      What are the variables that control these events? Experimental
      techniques in the study of protein folding often involve
      "denaturation" and "renaturation" of proteins in vitro.
      Denaturation is the elimination of the folding of a protein by
      changing ambient conditions such as temperature and pH, and
      renaturation is the refolding of the protein molecule into the
      native state following restoration of the original ambient
      conditions. ... ... Govindarajan and Goldstein (University of
      Michigan, US) present a theoretical analysis of current ideas
      concerning protein folding. In 1969, C. Levinthal pointed out
      that it is impossible for an unfolded protein to find the native
      state (its final configuration) by randomly searching through the
      entire space of possible conformations. This led Levinthal to
      postulate that a protein must follow a specific path to the final
      configuration, and therefore folding must be under kinetic
      control (i.e., under the control of a specific sequence of
      reactions). According to Levinthal, if the final folded state
      turned out to be one of lowest configurational energy, it would
      be a consequence of the biological evolution of specific chemical
      reaction sequences ("kinetic control"), and not of physical
      chemistry and the laws of thermodynamics ("thermodynamic
      control"). In contrast to this idea of Levinthal, C. Anfinsen in
      1973 concluded from the results of his numerous denaturation-
      renaturation experiments that the native state of the protein is
      indeed the global minimum of free energy, a conjecture that he
      called the "thermodynamic hypothesis" of protein folding. The
      debate between these two viewpoints of kinetic control and
      thermodynamic control has continued for more than two decades,
      with numerous experimentalists and theoreticians investigating
      whether proteins reach their global free energy minimum in a
      pathway-independent manner under thermodynamic control, or
      whether the protein molecule follows a specific pathway to a
      possibly local free energy minimum under kinetic control.
      Govindarajan and Goldstein now report an exploration of the
      validity of the thermodynamic hypothesis of protein folding by
      simulation of the evolution of protein sequences, investigating
      whether what is proposed by the thermodynamic hypothesis could
      result through the process of protein evolution, the approach
      involving certain assumptions concerning the effects of random
      mutations on protein evolution. The authors report that their
      results suggest that even if protein folding is under kinetic
      control, a specific kinetic sequence will evolve so that the
      native state of the protein molecule is most often the state of
      minimum free energy. They point out that one consequence of this
      is that theoretical methods that predict protein structure by
      means of algorithms and search strategies not apparently
      available to the protein itself may still be relevant as long as
      the model produces an eventual state of minimum free energy.
      QY: Richard A. Goldstein (richardg@...)
      (Proc. Natl. Acad. Sci. US 12 May 98 95:5545)(Science-Week 26 Jun 98)
      -------------------Related Background:ON SIMULATED EVOLUTION AND PROTEIN
      FOLDING
      ... The "bioinformatics" approach is based on the idea of
      recognition and identification in a protein of a new sequence of
      amino acids similar or identical to other sequences in other
      proteins for which structure and function are known. But this
      approach encounters difficulties because of a lack of
      understanding of what features of sequences have evolved to
      encode stability and fast folding in proteins, and a lack of
      understanding of which features are functional and which features
      are adventitious. Better understanding of general principles that
      govern kinetics and thermodynamics of protein folding can help to
      reveal the signatures of protein sequences that are related to
      folding. ... ... Mirny et al (3 authors at Harvard University,
      US) report a study of sequences of fast-folding model proteins 48
      residues long, the sequences generated by an "evolution-like
      selection" toward fast folding. They report that such fast
      folding model proteins exhibit a specific folding mechanism in
      which all transition state conformations share a smaller subset
      of common contacts (folding nucleus). The authors suggest their
      results and analysis imply that for each protein structure there
      is a small number of positions that are most crucial for fast
      folding into that structure. Protein sequences that fold fast
      into that structure may have evolved by placing into those
      strategic folding-nucleus positions amino acids that provide
      stabilization of the folding-nucleus.
      QY: Eugene I. Shakhnovich (shakhnov@...)
      (Proc. Natl. Acad. Sci. US 28 Apr 98 95:4976)(Science-Week 12 Jun 98)
      -------------------Related Background:
      BROWNIAN DYNAMICS SIMULATIONS OF PROTEIN FOLDING
      Protein folding occurs on a time scale ranging from milliseconds
      to minutes for a majority of proteins. Computer simulation of
      protein folding, from a random configuration to the native
      structure, is nontrivial due to the large disparity between the
      simulation and folding time scales. In order to overcome this
      limitation, simple models with idealized protein subdomains,
      e.g., the diffusion-collision model, have gained some popularity.
      The diffusion-collision protein-folding mechanism postulates the
      early-stage formation of fluctuating quasiparticles (micro-
      domains), which may be incipient secondary structures (alpha-
      helices and beta-sheets) or hydrophobic clusters. These micro-
      domains move via diffusion, and their coalescence leads to the
      formation of folded proteins. Thus, the diffusion-collision model
      reduces the complexity of the folding process from a consider-
      ation of individual amino acids to that of the properties of a
      few microdomains and their interactions. ... ... Rojnuckarin et
      al (3 authors at 2 installations, US) present an analysis of the
      folding of a 4-helix protein bundle within the framework of a
      diffusion-collision model. Even with the simplifying assumptions
      of a diffusion-collision model, a direct application of standard
      Brownian dynamics methods would consume 10,000 processor-years on
      current supercomputers. The authors circumvented this difficulty
      by invoking a special Brownian dynamics simulation. They report
      that a coarse-grained (i.e., crude) model of the 4-helix bundle
      can be simulated in several days on current supercomputers, and
      that such simulations yield folding times that are in the range
      of time scales observed in experiments.QY: Sangtae Kim (kim01@...)
      (Proc. Natl. Acad. Sci. US 14 Apr 98 95:4288)(Science-Week 15 May 98)
      -------------------Related Background:
      A MODEL FOR BETA-HAIRPIN FOLDING IN PROTEINS
      To be biologically active, proteins must adopt specific tertiary
      configurations, a specific "folding". Although many natural
      proteins spontaneously refold once they have been forced to
      unfold, synthetic proteins are often produced in an insoluble
      unfolded state and are thus inactive and useless until correctly
      folded. One important aspect of protein folding is the kinetic
      process, the rate at which folding occurs. Were a single
      conformation to be found by random searching of all the possible
      conformations, the number of years required would range from
      10^(7) to 10^(66). In actuality, protein folding occurs on the
      scale of microseconds, so there is clearly much yet to be learned
      about these macromolecules. Probabilistic analysis of the
      kinetics and energetics of a system of entities can be made
      within the framework of the theory of statistical mechanics, and
      the application of this theory is an important part of current
      research into protein folding. In general, protein chains fold
      into alpha-helices or beta-sheet structures, and the minimal
      beta-structural element is the "beta-hairpin", a turning of the
      polypeptide chain that has the shape of a hairpin. As far as
      experimental methods are concerned, analysis of folding kinetics
      in response to temperature variation is one of the key experi-
      mental procedures, and there are now sophisticated methods for
      temperature control provided by the coupling of computers and
      laser physics. One such method is laser "temperature jump"
      spectroscopy, which involves jump-heating (jump-discontinuity
      heating) of a small volume of aqueous solution in a short time
      domain coupled with spectroscopy in some part of the electro-
      magnetic spectrum. Munoz et al (4 authors: National Institutes of
      Health, US) used a nanosecond laser temperature jump apparatus
      coupled with laser fluorescence excitation to study the kinetics
      of folding of a protein beta-hairpin consisting of 16 amino acid
      residues, and they report that folding of the beta-hairpin occurs
      at 6 microseconds at room temperature, which is 30 times slower
      than alpha-helix formation. The authors offer a statistical
      mechanical model that provides a structural explanation for
      theirobservations.
      QY: Victor Munoz [vmunoz@...]
      (Nature 13 Nov 97) (Science-Week 5 Dec 97)-------------------Related
      Background:
      A SYNTHETIC OLIGOMER THAT MIMICS PROTEIN FOLDING
      The existence of helical folding in polymers such as proteins and
      nucleic acids is of extreme importance in biological systems, but
      biological polymers are not the only polymers to assume such
      special folding arrangements. Beta-peptides, for example, non-
      biological polymers synthesized from beta amino acids, form
      helices stabilized by hydrogen bonds. Now Jeffrey S. Moore et al
      (University of Illinois Urbana-Champaign, US) report that syn-
      thetic oligomers with an all-carbon backbone, linear phenyl-
      acetylenes with ester-substituted benzene rings linked to one
      another by acetylene groups, spontaneously fold into a stable
      helical configuration in acetonitrile, and that this apparently
      involves a "solvophobic" mechanism similar to the hydrophobic
      collapse model of protein folding in water. In both systems, the
      phenylacetylene oligomers and biological proteins, hydrophobic
      groups associate to form a compact structure that excludes the
      solvent. The phenylacetylene oligomers have longitudinal cavities
      that might be used for binding metals and other reactive species.
      The authors also suggest such systems could be used in the design
      and construction of synthetic enzymes.
      QY: J. S. Moore, Univ. Illinois Urbana-Champaign, Chemistry (217)
      333-0722 (Science 19 Sep 97) (Science-Week 3 Oct 97)-------------------
      Related Background:PROTEIN-FOLDING MECHANISMS IN PROKARYOTES VS. EUKARYOTES
      In biological systems, proteins are the molecules that do most of
      the biological work, and the various proteins are the ultimate
      expression of the genome of any organism. As polymers, proteins
      are similar to the polymers known to polymer chemists, but the
      chemical activities of proteins (and their biological functions)
      depend mostly on higher-order folding into specific configur-
      ations rather than on quasi-crystalline backbone arrays, as is
      often the case in non-biological polymer chemistry. It is these
      specific configurations that are responsible for the important
      specificity and high catalytic power of the proteins that are
      enzymes. The configurations, in turn, are an ultimate result of
      amino acid sequences which form the backbone of proteins,
      sequences which are not simple, as are the backbone sequences of
      most non-biological polymers, but are specific, cryptic (coded),
      and heterogenous. It is now recognized that complex proteins
      usually have more than one folding domain, each involving a
      sequence of 100 to 300 amino acids. The entire folding
      architecture of a complex protein must be precisely constructed
      in order for protein functionality to exist. Which provokes the
      question of how the specific folding of particular proteins is
      ensured by the biological system. The answer is evident for
      simple proteins in vitro: the final configuration is
      predetermined by the amino acid sequence, there being a single
      energetically favored configuration that will always be attained
      at equilibrium. This is Anfinsen's Rule, first proposed by the
      protein biochemist C. B. Anfinsen more than 30 years ago. In
      vivo, however, and particularly for complicated proteins, the
      situation is more involved. This week W. J. Netzer and F. U.
      Hartl (Sloan Kettering Cancer Center, NY US; Max Planck Inst.
      Biochemistry, Martinsried DE) report an analysis of the
      differences between protein folding in prokaryotes (organisms,
      such as bacteria, without membrane-bound organelles such as the
      nucleus) and eukaryotes (organisms with membrane-bound
      organelles). Perhaps the most interesting difference is that in
      prokaryotes protein folding is delayed until translation (final
      synthesis by the ribosome) is completed (post-translational
      folding), while in eukaryotes folding of each protein domain
      occurs as each domain is translated (co-translational folding).
      One result is that new prokaryote proteins can often be
      misfolded. There are helper proteins at work in both prokaryotes
      and eukaryotes to chaperon the proteins to their final
      configurations, but there is still more possibility for errors in
      the prokaryotes. One important consequence of this analysis is
      that when bacteria are genetically engineered to synthesize human
      protein for clinical use, the susceptibility of prokaryote
      protein synthesis to folding errors must be considered.
      (Nature 24 Jul 97) (Science-Week 8 Aug 97)
      4. STRUCTURAL MECHANISMS OF ENDOCYTOSIS5. IMMUNOLOGY: T-CELL SYNAPSES
      6. ON DNA VACCINES
      =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
      IN FOCUS: ON THE GENETIC CODE VS. HUMAN LANGUAGE
      "The analogy between the genetic code and human language is
      remarkable. Spoken utterances are composed of a sequence of a
      rather small number of unit sounds, or phonemes (represented, at
      least roughly, by the letters of the alphabet). The sequence of
      these phonemes first specifies different words, and then, through
      syntax, the meanings of sentences. By this system, the sequence
      of a small number of kinds of unit can convey an indefinitely
      large number of meanings. The genetic message is composed of a
      linear sequence of only four kinds of unit. This sequence is
      first translated, via the code, into a sequence of 20 kinds of
      amino acid. These strings of amino acids fold to form three-
      dimensional functional proteins. Through gene regulation, the
      right proteins are made at the right times and places, and an
      indefinite number of morphologies can be specified. Thus in both
      systems a linear sequence of a small number of kinds of unit can
      specify an indefinitely large number of outcomes. But there is
      one respect in which the two systems cannot usefully be compared.
      In language, the meanings of sentences depend on the rules of
      syntax. These rules are formal and logical. In contrast, the
      'meaning' of the genetic message cannot be derived by logical
      reasoning. Thus, although the amino acid sequence of the proteins
      can be simply derived from the genetic message, the way they fold
      up to form three-dimensional structures, and the chemical
      reactions they catalyze, depend on complex dynamic processes
      determined by the laws of physics and chemistry. It does not seem
      possible to draw a useful comparison between the way in which
      meaning emerges from syntax, and that in which chemical
      properties emerge from the genetic code."
      -- John Maynard Smith and Eors Szathmary: _The Origins of Life_
      (Oxford University Press, Oxford 1999, p.169)
      [J.M. Smith is at the University of Sussex, UK; E. Szathmary is
      at the Institute for Advanced Study Budapest, HU]
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