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Enabling better crystal structures & better structure prediction. Can’t wait to see where folks take that! SFCalculator is implemented in PyTorch, TensorFlow, and JAX. Open Source. See biorxiv.org/content/10.1... for more info & github.com/Hekstra-Lab/... to get started. 4/4

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With SFCalculator you can also *train* structure prediction / generative models directly on X-ray data. As James Holton has shown, the data are much more accurate than the models. The result: experiment-based generative models for ensembles (not yet general!) 3/4

We can refine protein structures by searching the latent space of pre-trained generative models. Using a Boltzmann Generator (@franknoe) as an example, doing so yields models with good physics & data fit! 2/4

Crystal structures are *not* God-given truth. They approximate, w/ flaws & errors, X-ray diffraction data. AlphaFold etc. have been trained on structures, not data. SFCalculator now differentiably connects structures to diffraction data. What does this enable? 🧵 1/4 www.biorxiv.org/content/10.1...

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Fruit of a close collaboration with Rama Ranganathan's group, where Doeke, Ian (@kiwhite), and Rama first developed EFX, and BoRam worked tirelessly to grow crystals and analyze data. New hardware and software from @HekstraLab were critical for success!

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In evolution, members of a protein family are often variations on a theme. The dynamic states resemble stable states of other channels: The sequence of steps of ion permeation is conserved from channel to channel with variations in relative energy. 7/8

Does the channel itself move? Yes! It moves as the ions pass, differently depending on the direction of ion flow. This suggests how rectification (asymmetric currents) can evolve. 6/8

What do we see? K+ ions coming in, hopping, and leaving. We see the K+ ions move, putting on a new “coat” of water molecules as they exit. 5/8

The experiment in simple: a crystal between two electrodes; X-rays coming in from the side: 4/8

Crystals of NaK2K, (H/T Youxing Jiang @ UTSW), form an ideal starting point: all ion channel pores are easily aligned with electric field (E): half of them “up”, half “down”. The red spheres are K+ ions: 3/8

Key is EF-X, a technique in which we apply electric field (EF) pulses to protein crystals and see the resulting motions with X-ray pulses. Physiological electric field, temperature, and timescales are all accessible. 2/8

Now in Cell: K+ ion channels enable electric currents consisting of potassium ions to generate action potentials in heart, brain, and muscle. For the first time, we can now see these currents atom-by-atom. www.cell.com/cell/abstrac... 1/8

cell.com

Laue-DIALS: Open-source software for polychromatic x-ray diffraction data

Led by Rick Hewitt and Kevin Dalton, the result is Laue-DIALS, hosted by @rs-station.bsky.social at rs-station.github.io/laue-dials/. Wanna try this out but need advice? Please get in touch. Further upgrades coming soon! Read more at pubs.aip.org/aca/sdy/arti... 2/2

pubs.aip.org

Most x-ray sources are inherently polychromatic. Polychromatic (“pink”) x-rays provide an efficient way to conduct diffraction experiments as many more photons

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X-ray diffraction can access protein dynamics. Why so few datasets? One reason? Lack of powerful pulsed X-ray sources. XFELs are limited. Synchrotrons throw away >99% of photons. Working with Aaron Bewster (DIALS/LBNL) and BioCARS (biocars.uchicago.edu/) to change this! 🧵1/2

rs-station.github.io

laue-dials — laue-dials