Chairs: Mike Thorpe, Arizona State University Anders Carlsson, Washington University at St. Louis

1. The Role of Theory in Biological Physics and Materials: A report to the National Science Foundation. Chairs: Mike Thorpe, Arizona State UniversityAnders Carlsson, Washington University at St. Louis

2. Meeting held in Tempe • 16 – 18 May 2004 • 62 participants • Bruce Taggart, NSF Daryl Hess, NSFDenise Caldwell, NSFKamal Shukla, NSF Jiayin (Jerry) Li, NIGMS, NIHJohn Whitmarsh, NIH Robert Eisenberg, APS Charles Day, Physics Today

3. 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?

4. Outline • Biomolecules • Supramolecular Assemblies • Systems Biology • Education and Infrastructure

5. 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

6. 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);

7. 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].

8. 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)].

9. Protons Moving in Biomolecules Molecular structure of the proton wire in gramicidin. [R. Pomes and B. Roux, Biophys. J. 82, 2304-2316 (2002)].

10. Interaction of Light with Biomolecules A molecular light switch made from oligopeptides [Yasutomi et al. Science 304, 1871, 1994 (2004)].

11. 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.]

12. Challenges in Biomolecules • Non-equilibrium statistical mechanics of small systems • Improved molecular force fields • Multiscale approaches

13. 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

14. 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].

15. 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]

16. Biomembranes and Biopolymer Materials Proposed raft structure with anchored proteins [R. G. W. Anderson and K. Jacobson, Science 296, 1821 (2002)]

17. 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)].

18. Viral Capsids DNA ejection from Bacteriophage T5 [courtesy of M. de Frutos, L. Letellier, and E. Raspaud, Orsay, France (2004)]

19. 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

20. 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].

21. Amyloid plaque from the human prion disease Kuru [from feany-lab.bwh.harvard.edu/link2/]

22. The Perutz zipper [C.A. Ross et al, Proc. Natl. Acad Sciences 100 (2003)

23. 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)].

24. Synthesis of New Materials Using Cellular Machinery

25. Challenges inSupramolecular 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?

26. 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

27. Life’s Complexity Pyramid [Z. N. Oltvai and A.-L. Barabási, Science 298, 763 (2002)].

28. Signal Transduction Network Bacterial Chemotactic System.

29. Gene Regulatory Network [U.S. Department of Energy Genomics: GTL Program, http://www.ornl.gov/sci/techresources/Human_Genome/graphics/slides/sciregulatory.shtml.]

30. Evolution: Phylogentics, Comparative Genomics, and Network Evolution The DNA packaged in the chromosomes contains the genes that encode for proteins.

31. 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

32. 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.

33. 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.

34. 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.

35. 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.

36. 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.

37. Report • biophysics.asu.edu/workshop/report.html • Thanks for your attention!