The Role of Theory in Biological Physics and Materials: A report to the National Science Foundation. Chairs: Mike Thorpe, Arizona State University Anders.

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

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)].

A molecular light switch made from oligopeptides [Yasutomi et al. Science 304, 1871, 1994 (2004)].

Interaction of Light with Biomolecules

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)]

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)].

Rod-Like Virus

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 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?

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!