BioXFEL Center Overview An STC Biology with X-ray lasers STCs - - PowerPoint PPT Presentation

A National Science Foundation Science and Technology Center

An STC Biology with X-ray lasers

BioXFEL Center Overview

A National Science Foundation Science and Technology Center

…innovative, potentially transformative, complex research

and education projects that require large-scale, long-term

• awards. STCs conduct world-class research through

partnerships among academic institutions, national laboratories, industrial organizations, and/or other public/private entities, and via international collaborations, as appropriate. They provide a means to undertake significant investigations at the interfaces of disciplines and/or fresh approaches within disciplines….. STCs investments support the NSF vision of advancing discovery, innovation and education beyond the frontiers of current knowledge, and empowering future generations in science and engineering.

STCs Mission

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3D Pictures and (later) Molecular Movies of Protein Structures Providing Insight into Biological Processes and Leading to Therapeutic Targets

• 2014 marks the 100th anniversary of crystallography
• It also coincides (roughly) with the emergence of free-

electron x-ray lasers (XFELs) as paradigm-shifting technology to:

• Determine molecular structures
• Monitor dynamics
• Enable time-resolved studies of functional

trajectories

Key Scientific Objectives

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• Spatially coherent 10fs x-ray pulses

containing > 1012 photons, enough to yield

• bservable diffraction from a crystal 10 unit

cells on edge.

• Repetition rate of 120 Hz, rising to 2700 Hz in

the next generation.

• Energies of 10kV - hard x-rays.
• Beam diameter as small as 0.1µm.
• Provides stunning set of opportunities.

The X-ray Laser Source

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LCLS

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Science Opportunities

• Crystallography

– Nanocrystals (NX) – smaller by 1000X than those used today; grow much more readily – Diffraction occurs before radiation damage takes effect – Non-frozen specimens – µs diffusion into NX allows new classes of time- resolved experiments

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Science Opportunities II

• Solution scattering

– Pulses freeze motions; no time averaging; time- resolved studies – Small numbers of particles can produce an

• bservable 2D pattern that contains much more

information than usual circularly symmetric one – Insightful math and algorithms may lead to recovery of diffraction pattern of a single molecule, thus to a structure – More signal than single particle scattering

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• Single particle imaging

– Ultimate nanocrystal: no crystallization problem – Full dynamic spectrum unfettered by lattice – Wet specimen at room temperature – Molecular movies – Experimentally most challenging

Science Opportunities III

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The three kinds of BioXFEL snap-shot diffraction experiments

Single particle per shot. Fast WAXS Single nanocrystal per shot.

Note dimensions in microns.

X-ray beam X-ray beam X-ray beam

Many X-ray shots do not hit a crystal

Many particles per shot

9

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Scientific and Technical Challenges

• Almost nothing from standard experiments

carries over to the XFEL. In SFX for example:

– Tiny crystals have to be delivered one at a time to coincide with the x-ray pulses – Diffraction patterns: one shot per crystal

• All spots are partials
• Fringes and other unfamiliar features
• Difficult solvent effects
• Pulse-to-pulse variation in intensity

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Scientific and Technical Challenges - II

• In SAXS a single fs-scale pulse illuminates a

volume containing a small number of molecules, producing a diffraction pattern that has azimuthal as well as radial variation.

– BioXFEL groups seek to recover the Fourier transform of individual molecules from these data; such transform can be phased to recover a molecular structure. – These molecules undergo structural fluctuations.

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Scientific and Technical Challenges - III

• In SPI for example:

– Scattering from single particle very weak – higher resolutions are far off. – Particle to particle variation requires smart binning to capture similar subfamilies. – Particles scatter in random orientations: correlating these will be very difficult. – Got to hit the beam…

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Key Center Objectives

• Nucleate a diverse community of scholars,

students, and interested laypersons that will support and develop the transformative capacities of XFELs.

• Make our research results and our technology

achievements widely available to all appropriate groups.

• Develop a broad range of collaborations

world-wide.

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BioXFEL Organizational Structure

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Graduate Students

• Grad students gain primary training in

program at home institution. We need to enrich and unite.

– Courses on BioXFEL topics – Center-wide professional development – GS get to be mentors as well as to be mentored – On-line journal club recorded for replay – Annual meeting

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• Insightful John has instituted collective

reviews of STC beamtime proposals for each cycle at LCLS.

– Merging proposals makes them better and improves chances of time being awarded. – The exchange of proposals is a powerful internal communication channel for BioXFEL. – Builds community.

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Steering Committee

Name Role Scientific Thrust Area Eaton Lattman Center Director John Spence CoPI, Scientific Director Sample delivery, SFX methods, analysis, theory Petra Fromme CoPI Structures and mechanisms in photosynthesis Abbas Ourmazd CoPI Single-particle Theory Edward Snell Participant Crystallization, SAXS George Phillips Participant Heterogeneity, dynamics Alexander Cartwright VPR UB Margarita Dubocovich Education Director Kenneth Tramposch Knowledge Transfer Thomas Furlani Computation Director Jill Szczesek Managing Director

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Steering Committee

• Committed to consensus management.
• Model of separate Center and Scientific

Directors proving effective.

• All major issues discussed by the SC, usually

by teleconference.

• Example: the saga of the budget cut that

tested the SC model, but never came to pass.

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Software

• Livermore Software conference

– Organized as a collaboration between the Physical Biosciences Division of LBNL, and BioXFEL. – A multi-day school & workshop with entire range

• f developers. Seminars on the latest XFEL

methods; opportunity for students to process real

• r example data with various programs.

– Course materials will be archived on the Web. – Another example of community.

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How are we doing?

• STC less than nine months old at time of review.
• Lots of good press - see

https://www.bioxfel.org/news.

• Before official award approximately 25 papers

involving one or more BioXFEL STC co-authors.

• Since the award there are at least 23 published

papers with four in press that are supported by and acknowledge the BioXFEL STC. Many of these are in high profile journals.

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How are we doing?

• 4-day Royal Society meeting on XFELs held in

October 2013 was co-organized by John Spence.

• Conference proceedings on line June 9, 2014 in a

special issue of Philosophical Transaction: 27 papers.

• 11 are co-authored by STC-supported

investigators, and an additional three are co- authored by close collaborators.

• This issue will be a central document in XFEL

science for years to come.

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How are we doing?

• BioXFEL technology critical to the field

– Weierstall’s lipid cubic phase “toothpaste jet” vehicle for the delivery of membrane protein crystals to the XFEL beam. – This protein-sparing device ➞ crystallography of many membrane proteins for which protein production has been a fatal bottleneck. – ASU is devoting major resources into providing LCP delivery systems to other institutions, and it providing tutorials so that others can make them independently. – Work is even beginning on fabricating them by high- resolution 3D printing. Parallel studies are already under way to develop high-viscosity, water-based jets for the study of crystals of soluble proteins.

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How are we doing?

• Major institutional collaborations

– SLAC and BioXFEL are having deep discussions about joint funding applications to enhance the LCLS, and actual submissions are sure to occur. – BioXFEL has stationed Dr. Marc Messerschmidt at DESY in part to help cement growing collaborations between the two institutions. – On every front BioXFEL is developing strong momentum in the world XFEL community. Not bad for a neonate. – Director is still having fun.