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The Role of Theory in Biological Physics and Materials: A report to the National Science Foundation. Chairs: Mike Thorpe, Arizona State University Anders Carlsson, Washington University at St. Louis Meeting held in Tempe 16 – 18 May 2004 62 participants Bruce Taggart, NSF Daryl Hess, NSF Denise Caldwell, NSF Kamal Shukla, NSF Jiayin (Jerry) Li, NIGMS, NIH John Whitmarsh, NIH Robert Eisenberg, APS Charles Day, Physics Today Questions What are the important problems in biology that can be solved with the help of theory? What types of theory are most useful in treating biological problems? What new physics and materials science can be learned by the study of biological systems? What types of educational opportunities and infrastructure support would be most helpful to nurture this community? Outline Biomolecules Supramolecular Assemblies Systems Biology Education and Infrastructure Biomolecules Fundamental building blocks of living cells Their role is felt across the entire hierarchy of biological order Physics has played a key role from the beginning in developing our understanding of biomolecules Physically based theoretical methods are increasingly used in biomolecular modeling Protein Structure The study of biomolecules was initiated with the double-stranded structure of DNA shown on the left and the original ball-and-stick model of myoglobin on the right the first 3D structure of a protein determined ( http://nobelprize.org/chemistry/laureates/1962/kendrew-lecture.pdf); Cellular Mechanics and Molecular Motors Schematic of thermal ratchets possibly related to molecular motors. The lateral bolts in frame (b) allow the ratchet to move to the right. [P. Nelson, “Biological Physics” (W. H. Freeman, New York, 2004), p. 414]. Bio-nano Devices Snapshot of an MD simulation of water molecules in a carbon nanotube that is similar to diffusion of water in aquaporin [G. Hummer, J. C. Rasaiah, and J. P. Noworyta, Nature 414, 188 (2001)]. Protons Moving in Biomolecules Molecular structure of the proton wire in gramicidin. [R. Pomes and B. Roux, Biophys. J. 82, 2304-2316 (2002)]. Interaction of Light with Biomolecules A molecular light switch made from oligopeptides [Yasutomi et al. Science 304, 1871, 1994 (2004)]. Elastic Properties and Strain The ribosome where proteins are assembled using instructions from the genetic code is one of the largest structures ever determined by X-ray crystallography. [J.H.Cate, M.M Yusupov, G.Z. Yusupova, T.N. Earnest, H.F Noller, Science 1999; 285:2095-104.] Challenges in Biomolecules Non-equilibrium statistical mechanics of small systems Improved molecular force fields Multiscale approaches Supramolecular Assemblies Assembly and function of supramolecular structures is crucial many functions - the cytoskeleton which determines cell shape and movement, lipid bilayers which demarcate the cell and its compartments, and multi-component assemblies forming complex machines Progress in understanding supramolecular assembly requires tools of biology, chemistry, physics, mathematics, and materials science Theory is crucial because probing the dynamics of function, assembly, and disassembly is difficult Electrostatics of Macro-ions in Aqueous Solution Complexes of DNA with multivalent cations at different concentrations of C+ and with proteins at different mono-valent salt concentrations. The electron micrograph is of Lambda bacteriophage genome condensed by multivalent particles [courtesy of J.-L. Sikorav, CEA-SACLAY, France]. Intracellular Networks of Semi-flexible Polymers Schematic of a semi-flexible polymer showing “wiggles” produced by thermal fluctuations. The external force increases the length R of the polymer by pulling out the wiggles. [Courtesy of F. C. MacKintosh] Biomembranes and Biopolymer Materials Proposed raft structure with anchored proteins [R. G. W. Anderson and K. Jacobson, Science 296, 1821 (2002)] Rod-Like Virus Self-assembly of Tobacco Mosaic Virus from solution of capsid protein plus RNA molecules [H. Fraenkelconrat and R. C. Williams, Proc. Nat. Acad. Sci. 41, 690 (1955)]. Viral Capsids DNA ejection from Bacteriophage T5 [courtesy of M. de Frutos, L. Letellier, and E. Raspaud, Orsay, France (2004)] Chromatin Structure Chromatin structure [P. Ridgway, C. Maison, and G. Almouzni, Atlas Genet. Cytogenet. Oncol. Haematol. (May 2002) http://www.infobiogen.fr/services/chromcancer/ Deep/ChromatinDeep.html Aggregation of Mis-folded Proteins Autocatalysis of the prion protein (normal-PrPc, infectious-PrPSc) at the monomer level (upper picture) or via aggregation (lower). [Courtesy of D. L. Cox]. Amyloid plaque from the human prion disease Kuru [from feany-lab.bwh.harvard.edu/link2/] The Perutz zipper [C.A. Ross et al, Proc. Natl. Acad Sciences 100 (2003) Precision Self-assembly of Organelles Origin of the helical shape of a flagellar filament [K. Namba and F. Vonderviszt, Quart. Rev. Biophys. 30, 1 (1997)]. Synthesis of New Materials Using Cellular Machinery Challenges in Supramolecular Assemblies Theories need to be developed at length and time scales appropriate for comparison with experiment Theory is especially useful in developing general pictures, ideas, and concepts. Methods are needed for dealing with nonequilibrium problems Key overriding question: what factors determine the dynamics and perfection of self-assembly? Systems Biology The ultimate many-body problem of living matter How does function emerge from interaction of numerous molecular components? Ranges from cell level to organismic and higher levels Life’s Complexity Pyramid [Z. N. Oltvai and A.-L. Barabási, Science 298, 763 (2002)]. Signal Transduction Network Bacterial Chemotactic System. Gene Regulatory Network [U.S. Department of Energy Genomics: GTL Program, http://www.ornl.gov/sci/techresources/Human_Genome/graphics/slides/sciregulatory.shtml.] Evolution: Phylogentics, Comparative Genomics, and Network Evolution The DNA packaged in the chromosomes contains the genes that encode for proteins. Challenges in Systems Biology Understanding specificity, robustness, and evolvability Develop methods for evaluating and studying modularity of biological systems Physics can guide biology in focusing study on a small number of key degrees of freedom Overriding Scientific Themes Non-equilibrium thermodynamics. Almost all biological phenomena are inherently non-equilibrium, but most condensed-matter and materials theory has focused on equilibrium problems. Study of biology and biological materials could aid development of conceptual structures for non-equilibrium phenomena. Self-assembly. Seen on an enormous range of length scales, and is often highly accurate. Self-assembling materials may well be a major thrust in future materials development. Education and Infrastructure Biological physics is expanding very rapidly Existing efforts, such as graduate training programs and summer schools, point the way to more comprehensive efforts. Community-Building Bring physicists and biologists together. Define important problems of common interest for biologists and physicists Provide a forum and environment to nuture innovative new approaches to biology that address the fundamental issues of living matter Establish interdisciplinary (and theory/experiment) collaboration Provide education in biological problems for graduate, postdoctoral and more senior level physics researchers, and education in quantitative methods and physics approaches for biologists. Recommendations The expansion of NSF joint funding linking the NSF, especially DMR, with the NIH. The establishment of regional research and training centers in biological physics and materials to bring together biologists and physicists. The expansion of postdoctoral fellowships supporting transitions into biological physics. The development of more summer schools, internet resources and textbooks. Support for sabbatical visits to institutions with active biological physics and/or biology programs. Recommendations Undergraduate and graduate courses contain more examples of physics being used in biology and vice versa. Encourage more flexibility in graduate programs, especially in qualifying procedures in masters and doctoral programs. Report biophysics.asu.edu/workshop/report.html Thanks for your attention!