Hekstra Lab
@HekstraLab
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Research group of Prof. Doeke Hekstra | Harvard Department of Molecular & Cellular Biology
Cambridge, MA
Joined January 2021
Can AlphaFold refine structures for X-ray & Cryo-EM/ET data? Now it can! Great collab with @MoAlQuraishi and Randy Read, led by Alisia @FadiniAli and @mhli41. Preprint: Summary 🧵below. Code to follow. .
Structural biology is in an era of dynamics & assemblies but turning raw experimental data into atomic models at scale remains challenging. @mhli41 and I present ROCKET🚀: an AlphaFold augmentation that integrates crystallographic and cryoEM/ET data with room for more! 1/14.
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Led by Rick Hewitt and Kevin Dalton, the result is Laue-DIALS, hosted by @rs-station.bsky.social at Wanna try this out but need advice? Please get in touch. Further upgrades coming soon! Read more at 2/2.
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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 ( to change this! 1/2.
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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 for more info & 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 @JHoltonMADSci has shown, the data are much more accurate than the models. 3/4
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We can refine protein structures by searching the latent space of pre-trained generative models. Using a Boltzmann Generator (@FrankNoeBerlin) as an example, doing so yields models with good physics & data fit! 2/4
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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
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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! 8/8.
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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
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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
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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
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The experiment in simple: a crystal between two electrodes; X-rays coming in from the side: 4/8
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Crystals of NaK2K, (H/T Youxing Jiang at @UTSouthwestern), 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
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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.
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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. a thread🧵 1/8.
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Thanks @MCB_Harvard for the news feature about our latest paper, out now in Cell!.
Watching Ion Channels in Action @HekstraLab @RachelleGaudet @msm91283 @mklureza @UChicago @Stanford @HarvardCCB @Harvard @HarvardGSAS
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RT @AmmaarSaeed3: Excited to share my undergraduate work @biorxivpreprint w/ @HekstraLab and @mklureza: "Mapping protein conformational lan….
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