BIOMOLECULAR MATERIALS

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Biomolecular Materials—BESAC 2/25/02

BIOMOLECULAR

MATERIALS

San Diego, January 13-14, 2002

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• Doubletree Golf Resort,

• San Diego, California

• January 13-14, 2002

• Co-chairs:– Sam Stupp, Mark Alper

Biomolecular Materials

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Invited Speakers

Lia Addadi Weizmann InstitutePaul Alivisatos Lawrence Berkeley LabHagan Bayley Texas A & MAngela Belcher University of Texas, AustinCarolyn Bertozzi Lawrence Berkeley LabJean Fréchet Lawrence Berkeley LabReza Ghadiri Scripps Research InstituteWolfgang Knoll Max-Planck- MainzChad Mirkin Northwestern UniversityCarlo Montemagno UCLA

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Invited Speakers

Thomas Moore Arizona State Daniel Morse Univ. Calif. Santa BarbaraDavid Nelson Harvard UniversityCyrus Safinya Univ. Calif. Santa BarbaraPeter Schultz Scripps Research InstituteNed Seeman New York UniversityDouglas Smith Univ. Calif. San DiegoViola Vogel University of WashingtonUli Wiesner Cornell UniversityXiaoliang Sunney Xie Harvard University

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Workshop Focus

• Specific research activities and goals

• Nature of research in biomolecular materials

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Materials and Biology

• Biomaterials– Materials, of any origin, designed for use as

implanted medical devices or prostheses

• Biomolecular/Biomimetic Materials– Materials, designed for non-medical

applications, whose structure or synthesis is derived from or is inspired by biology

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“Biomedical” Materials

• DOE mission does not include biomaterials research that is supported by NIH for biomedical applications.

• But NIH does not support some aspects of biomedical research--for example instrumentation.

• DOE program could support spin-offs into biomedicine of materials and chemical sciences research on instrumentation development

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• Made by living organisms

• Made by living organisms and then modified in the laboratory

• Made by living organisms that have themselves been modified

• Made in vitro by a process that is unique to a living organism

• Made in vitro by a process patterned after that employed by a living organism.

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Use molecules, structures, processes, concepts of

biological systems as the basis for novel materials

and devices to be used outside of living systems.


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Biology Has Attracted the Attention of Physical Scientists

Properties, functions and structures in living organisms are seen as attractive for non-biological applications…

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What Do Organisms Do?

• Atomic level control of structure• Adaptation to the environment• Amplification of signals• Benign processing conditions• Bio-compatibility—interfaces with living and

non-living materials. • Biodegradable materials• Biopolymers: control of properties -many

monomers, defined length

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• Color control, alteration, iridescence =>color by angle• Catalysis/enzymes • Combinatorial synthesis• Computation• Conformational change• Energy conversion• Evolution• Extreme environments• Hierarchical construction

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• Lightweight materials• Lubricants• Machines: motors, rotors, pumps, transporters, tractors,

springs, ratchets, contractile proteins • Mass production• Materials by design • Membranes-selective, active transport, barriers• Molecular recognition • Multi-functional materials• Nanoscale synthesis and function

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• Optical materials• Self-assembly• Self healing, repair, damage/fault resistance/tolerance• Smart materials• Sensors• Structural materials• Systems: shark skin, lotus leaves reject dirt-fine surface

roughness not bind• Templated synthesis • Transport systems

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Biology Has Attracted the Attention of Physical Scientists

…and biologists and others have developed the tools to understand and manipulate biological structures and processes and to mimic biological concepts.

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• Genetic/protein engineering• Cloning• Structural biology• Protein purification• DNA sequencing• Protein sequencing• DNA synthesis Protein synthesis• Carbohydrate analysis/synthesis• Phage display• …• …

How Are Biological SystemsManipulated and Analyzed?

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But This Is Not Totally New

Bone, teeth, eggshells, enzymes have been studied for decades with the goal of using them or their mimics in non-biological applications.

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Workshop Conclusion

It is now not only appropriate but important to support research in biomolecular materials for non-biomedical applications

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Is Biomolecular Materials Research Different?

• In many areas of materials research, a particular combination of elements, processed in a specific manner is shown to have important properties.

• The origin of this discovery could have been experiment or theory.

• The focus of research then shifts to understanding why those properties arise and identifying altered compositions or processing conditions to enhance the them further.

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Is There a BiomolecularMaterial?

• “Biomolecular materials” is a catch-all phrase for an enormously wide variety of research areas--

• The research approach is different for:

– use of a molecule

– adaptation of a molecule

– use of a concept

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What is Different about Biomolecular Materials Research

• In biomolecular materials research, the ideal already exists*.

• An existing material, with its given properties, is used in a non-biological environment.– DNA as a scaffold.– Kinesin as a nano-scale tractor

• Alternatively it is mimicked for use in non-biological environments. – Photosynthetic mimics-energy transduction – Bone mimics-structural properties

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Biological Systems are Extremely Complex

• In many cases, we do not know what molecules are involved in achieving a property.

• Where we do, we often don’t know their structure.• Thus, we know far less about these molecules and

processes than we do about semiconductors, metals, ceramics.

• In most areas, applications of biomolecular materials lag far behind conventional materials.

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Must Our Approach to Research be Different?

• In superconductivity, we can look for new compositions without truly understanding what is going on.

• In biomolecular materials, we often need to understand much more than we do before we can make new materials.

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• We don’t really know what gives bone its exceptional properties--How do we construct something similar?

• We don’t know how molecules find their three dimensional shape--How can we design self- assembling systems that depend on precise docking of components?

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• We don’t really understand how molecular motors work. How do we make more?

• We don’t really understand how proteins fold--then how, other than by trial and error, can we design proteins that specifically bind semiconductors.

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At least until now, research into, for example, the mechanism of myosin action, the basis for the development of nano-machines, was regarded as biomedical (NIH) while research into the mechanism of superconductivity, required for the development of room-temperature superconductors, was regarded as materials science.

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Workshop Conclusion

Basic research in biology, where it is notunreasonable to expect that the resultingunderstand will be critical to our learning tomanipulates these systems for non-medicalapplications, must be regarded as a legitimatearea for DOE-BES support.

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Are There Other Differences?

Biology is not like high-Tc superconductivity. It is like physics--a large collection of very different research topics unified, to some extent, by a common culture, way of thinking, research approach. But few of these topics are sufficiently mature to allow a reasonable argument that “materials” are in the wings.

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The Problem

The “correct” path for research support is difficult to identify. Do we pick areas of “greatest” interest, do we pick areas that appear to be furthest along, or do we fund specific research activities across a broad range of topics, based solely on the scientific merit of the individual proposals?

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Workshop Conclusion

• A research portfolio in biomolecular materials must be broad, and project selection should be based primarily on individual scientific merit; “picking applications winners” now is impossible.

• A research portfolio in biomolecular materials must be sufficiently narrow, focused on a number of themes, so that a critical mass for collaboration and interaction is created.

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Are there Barriers to Developing a Successful Program

• Physical scientists do not “know” biology– Protein folding

– Enzyme catalysis

– Metabolism

• Biologists don’t know applications other than pharmaceuticals and biomaterials

• Few collaborations between biology and the physical sciences have existed except for the application of instruments to the study of biology.

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Workshop Conclusion

• A new generation of multidisciplinary students needs to be trained.

• Research proposals that are supported should support the training of students.

• Research proposals that are supported must demonstrate the participation of experts in both the relevant materials/chemistry and the biology.

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What are the top 3 to 5 future opportunities

at the interface between the biological and

physical sciences?

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Workshop Conclusion • Self- and TemplatedAssembly and

Biomimetics– A. Bio-inorganic systems– B. Bio-organic systems

• Biomolecular Functional Systems

• Cell Engineering and Cells in Artificial Environments

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Biomolecular Functional Systems

• Motors: Flagella• Rotors: ATP synthase• Tractors: Kinesin• Catalysts: Enzymes• Energy Transducers: Photosynthetic Center• Gates and Transporters: Membrane proteins

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Schultz

Enzyme Engineering

Schultz

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Enzyme Catalyzed Mineralization

Morse

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Fluorescence Image of Single Enzyme Molecules

Fluorescent Cofactor:

Flavin Adenine Dinucleotide (FAD)

OH OH

NH2

OH

H

OH

OH

O

O N

N

N N OP

OP

OO

OH OH

O O

N

N

N

N

CH 3H 3C

OH OH

NH2

OH

H

OH

OH

O

O NN

N N OP

OP

OO

OH OH

O O

NN

NN

CH3H3C

FAD

Protein

Xie

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Enzyme Catalysts

• Dendrimers as artificial enzyme mimics--– Bind substrate– Light activated catalysis– Expel product

Frechet

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Biomolecular Materials—BESAC 2/25/02 Vale

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Kinesin As a Tractor

• Direct motion along defined track• Loads and unloads cargo• Turn on and off/ control speed

– Light activation of caged ATP – Enzyme mediated ATP degradation

Vogel

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FF11-ATPase-powered Nano--ATPase-powered Nano-

propeller Systempropeller System

• Mean angular velocity = ~4.4 Hz

•Maximum angular velocity = 8.5Hz

•Functional Duration = >2 hrs

•Power = ~120 pN·nm per revolution

•Efficiency = ~82%

Montemagno

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Photon Fueled Biomolecular Motor Powered NEMS

Montemagno

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Photosynthetic Mimics

• Supramolecular structures of antenna systems and artificial reaction centers capable of photoinduced electron transfer over 50Å.

• Insert in membrane and couple created redox potential to production of proton motive force with the capability of doing “work”--transport, gradients, motors.

Moore

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Eric Gouaux, Columbia

-Hemolysin (-toxin)

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-Hemolysin (-toxin)

Bayley

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BIOMOLECULAR

MATERIALS

San Diego, January 13-14, 2002

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Biomolecular materials are chemicals that made by living organisms. As such, their study is no different from the study of polymers, dendrimers, or nanocrystals.

Structure defines function,different structures define different functions. Theory, modeling, synthesis, chacterization can be applied to peptide polymers, highly branched carbohydrates, or amphipatic lipids.

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• Make proteins with aminoacid seqencesthat providehigh stregth

• Make proteins with moretan 20aminoacids--Schultz.

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• On another level, nature has been able to design molecules using synthetic tricks we cannot recreate now---defined length, defined sequence, multple monomers.

• Thus use natures synthetic techniqujes or be challenged to develop othertechniquesto achieve end result

• Use nature’s materials, fiind ways to make them in larger amounts-spider silk.

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• Nature achieves properties goals through novel techniqes --e.g. easily broken/remade bonds in bone to asorb aenegy ndnot break.

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• Nature acieves things through exceptional lvels of complxty that we simply now need to understand

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• Fnctona materials include enzmes

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Research Area Titles

Self- and TemplatedAssembly and BiomimeticsA. Bio-inorganic systemsB. Bio-organic systems

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• Biomolecular Functional Systems• Define research area: Natural systems that

perform biological functions are selected and their components are chemically defined. These are the components that will map into functional units, which will in turn map into systems and emergent properties.

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• Controlling kinesin by Reversible Disulfide Cross-linking: Identifying the Motility-producing Conformational Change

• Michio Tomishige and Ronald D. Vale• J. Cell Biol. 151, 1081, 2000

• Engineering the Processive Run Length of the Kinesis Motor

• Kurt S. Thorn, Jeffrey A. Ubersax, and Ronald D. Vale• J. Cell Biol. 151, 1093, 2000

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• Biochemists, molecular biologists, cell biologists focus primarily on developing a molecular level description of their systems. With the exception of pharmaceutical development, they rarely view biological systems as models for in vitro materials or devices.

• Chemists, physicists, materials scientists are not trained in the biological sciences.

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Biomolecular materials

Are there lessons to be learned from previous successful and unsuccessful efforts to stimulate research efforts at this interface?

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• Biomolecular materials studies:– Ceramics---teeth– Magnets--magnetotactic bacteria– Polymers--proteins, carbohydrates, nucleic

acids– Electronic materials--neurons

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• Grants requiring interdisciplinary collaborations foster teams with breadth of required expertise.

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Recommendations-Draft

• Spin off instrument development to biomolecular materials and also to biomaterials, in areas not funded by NIH

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Driver: AFOSR “Biological Infrared Sensing Initiative”•Improve the AF’s infrared detection capability using biomimetics

•Does underscore the importance of IR detection in AF systems

Why:•Extremely sensitive (0.003˚C*)•No external cooling required•Fundamentally different mechanism of IR detection •DTO not met with current technology—cost prohibitive

Biological Infrared Sensing Program

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TOPICAL GROUP TITLES

• Bio-inorganic systems

• Self-Assembly and Biomimetics

• Biomolecular Functional Systems

• Cell Engineering and Cells in Artificial Environments

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Define the Area• Describe the links to biology

• What are the unifying themes of this topic

• What is the nature of the science

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Are These Attributes Accessible?

Can we exploit these and other biological

concepts, systems, structures, molecules

in the development of “extra-biological”,

non-biomedical systems?

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Where is the Path?

What basic research, in which of

the disciplines, needs to be done

to get us there?

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Where is it Going

Where do you think the area will be in 5 years, 10 years?

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Are There Barriers to be OvercomeWhat organizational, cultural or other

barriers hinder the establishment of research

programs at the interface between the biological

and the physical sciences? Are there lessons to

be learned from previous successful and

unsuccessful efforts to stimulate research efforts

at this interface.

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Are There Realistic Applications in the Energy Sciences?

• Much has been promised

• New discoveries make headlines

• What is truly within reason

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How Do We Report on a Research Area?

1.Introduce the underlying biology of the particular area of study (bone is a material that performs the following functions in an organism, is made this way, has this structure, these properties, etc.)

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2. Describe, from the materials or chemical

sciences (non-biomedical) perspective, some

of the most exciting recent work in

understanding or manipulating the properties

of these systems, structures, molecules --

with lots of pretty images

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3. Discuss the major research directions challenges

in this particular area, especially with regard to the

various disciplines that need to be brought to bear

on it, the existing tools that need to be applied and

the new tools that need to be developed.

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4. Some limited speculation on the potential

impact of the study, characterization and

manipulation of these biological systems on

applications in the materials or chemical

sciences.

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What are the Priorities?Within your own general area of expertise,

broadly defined, which are the biological systems,

structures, molecules whose further study,

characterization and manipulation are most likely

to give us important new insights into our view of

them as materials or chemical agents rather than

as biological or biomedical components.

?

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• What would you really like to understand in the long run

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Example answers:•the study of the structure and properties of

bone, which would help us understand composites with the characteristic and very attractive mechanical properties of bone.

• the study of the structure and properties of biological membranes, which would help us understand methods of separation, or the creation and maintenance of chemical and potential gradients .

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