October 13, 2025

Run 26 Mail-in small-molecule serial femtosecond crystallography (smSFX) at LCLS

LCLS Mail-in smSFX Sample Submission Guidelines for Run 26 (Dates TBD)

Submission Deadline: 1st February 2026 (11 pm PDT)

Following on from the announcement of the pilot program for mail-in small-molecule serial femtosecond crystallography (smSFX) experiments planned for January 24-30 2026, submissions are now open for users to submit prepared samples to LCLS staff scientists for screening and possible structure solution during subsequent beamtime in Run 26, provisionally scheduled to take place between March and July 2026.

X-ray FEL serial diffraction is a general, high-throughput method for chemical crystallography using microcrystalline samples. About 50 small-molecule structures have been determined so far with X-ray FEL diffraction. The LCLS mail-in pilot program is designed to offer this powerful method as a simple, accessible service for researchers in chemistry and materials science.

How to Submit Mail-in Requests

The program works through a pipeline of a few simple steps (see Figure 1).

Mail-in SFX pilot program overview diagram
Figure 1. Mail-in SFX pilot program overview
  1. Register in the Universal Proposal System (UPS): Registration Guide
  2. Submit a mail-in request through the UPS: https://ups.servicenowservices.com/ups
    • Currently we are aggregating submissions by the following material classes:
      • Hybrid Materials
      • Metal-Organic Frameworks/Covalent Organic Frameworks
      • Inorganic Covalent Solids
      • Molecular Organic Crystals
    • Each aggregated proposal will highlight the samples that best represent each material class for scientific peer review. If samples could potentially be represented by multiple material classes, please submit a separate form for each different class. If your materials are not captured by any of these classes, please reach out to us to describe the material class that would best encapsulate your samples before submitting.
    • Note: Requests must be submitted before the deadline of 1st February 2026 (11 pm PDT) to be considered for beamtime during Run 26. The following step-by-step submission guide and submission example are provided to help with your submission.
  3. Once your request is submitted, and following the announcement of beamtime, you can submit your most current sample safety spreadsheet and supporting information for our team to assess sample feasibility and safety.
    • Samples must be provided for review one month before the scheduled beamtime to give our staff time to review all the information and provide feedback. Please carefully read through our feasibility and safety process to see the supporting documents we require and to download the required sample safety spreadsheet.
  4. Following review, you will receive an email specifying which samples have been approved to participate in the program and feedback for the ones that cannot. Approved samples can then be shipped (and no unapproved samples will be accepted).
  5. Wait for results! Depending on the total number of users and samples submitted, users should be able to expect results within a month of beamtime. Feedback for samples that do not result in a structure solution will also be provided with recommendations for future preparations.
    • Note: If your data results in publication please acknowledge our facility and cite the papers as follows.
    • For additional information and to submit supporting documents please see our contacts list.

Feasibility and Safety Review

Once beamtime is announced you can submit your most current sample list and supporting information for our team to assess samples feasibility and safety.

Note: No new samples will be reviewed within one month before the beamtime starts to give our staff time to review all the information and provide feedback.

Pre-Characterization of Samples

Over the course of developing this smSFX pilot program, we have determined ways to provide a good approximation of sample compatibility with our instrument. Two types of material characterization are necessary for samples before they can be examined at the mail-in beamtime: optical/scanning electron microscopy (SEM) for size determination and powder X-ray diffraction (pXRD) for crystallinity.

Note: Only samples that demonstrate an average 1 to 20 𝜇m size along at least two dimensions via microscopy and sharp diffraction peaks via pXRD can participate in the program. If your samples don’t meet these qualifications but you think that our program is your only chance at structure solutions please reach out to us and we can discuss it.

Optical/Scanning Electron Microscopy for Size Determination

smSFX is most compatible with microcrystalline powders in which the average crystallite is between 1 to 20 𝜇m in size along at least two dimensions. Thickness measurements are not required but our sample preparation methods do require manipulation of the sample. Ultrathin and fragile samples where the crystal lattice can be damaged from handling are not recommended unless the samples can be prepared on our fixed-target chips and shipped to us. Microscopy provides us with an estimate of the average crystallite size in the sample. Samples where the average crystallite size is below 1 𝜇m in at least two dimensions are classified as nanocrystals. Due to the current minimum beam spot size available at the MFX and XCS endstations and the ambient nature of our sample environment, diffraction data quality from nanocrystalline samples may be compromised. Samples where the average crystallite size is above 20 𝜇m are better suited for measurement at a synchrotron source with serial crystallography capabilities. Bragg diffraction from larger crystallites will cause permanent damage to our detectors due to the high-power density of the XFEL pulses and the presence of strong scatterers (i.e. metals) in most small molecule samples.

Electron microscopy, such as SEM, is ideal as it will provide the most information about crystal size and morphology. SEM can also give information about crystal aggregation, presence of polycrystalline clusters, or accumulation of amorphous side-phases that could impact the XFEL diffraction data quality. Well-separated crystals allow for uniform distribution of the sample using our fixed target sample delivery system. If the sample agglomerates in our fixed target media, the single-shot images will look more like powder rings from clusters of randomly oriented microcrystals as opposed to one single-shot image corresponding to one randomly oriented crystallite. SEM is recommended for additional screening purposes, but optical microscopy is the minimum requirement for initial feasibility review. See Figure 2 for examples of crystal morphologies that are both unsuitable and suitable for smSFX.

Examples of crystal morphologies that are both unsuitable and suitable for smSFX
Figure 2: Examples of crystal morphologies that are both unsuitable and suitable for smSFX. A. This sample is a polycrystalline aggregate, along with what seems like amorphous side reactions. B. Multiple morphologies, along with similar polycrystalline aggregates and what seem like nanoparticles from unreacted precursors. C. No obvious facets that suggest crystallinity. D. Sharp facets, uniform morphology, distinct single crystallites. E. Similar case with uniform morphology, distinct single crystallites and sharp facets indicating crystallinity.

Note: If your samples contain crystals that are larger than 20 𝜇m they are a good candidate for a synchrotron light source. We are currently working on a serial crystallography partnership with the Gemini MX beamline (BL2.0.1) at the Advanced Light Source (see link below). We hope to be able to transfer samples that are too large for us to accept to them starting in February. If you are interested in this as an alternative please check the appropriate box in your UPS submission.

https://als.lbl.gov/beamlines/2-0-1/

Powder X-ray Diffraction for Crystallinity

pXRD is the best conventional determination for crystallinity. If a sample does not produce sharp diffraction peaks using a benchtop diffractometer or a synchrotron powder diffraction beamline, it is also unlikely to diffract with sufficient quality to be processed and solved at an XFEL. Ideally, peaks should be sharp and relatively well defined (shown in Figure 3).

Examples of pXRD for the same sample with varying degrees of crystallinity
Figure 3: Examples of pXRD for the same sample with varying degrees of crystallinity. The sample corresponding to the top diffraction pattern is of suitable crystallinity for measurements; The middle sample is potentially acceptable given suitable crystal size and morphology; the bottom is unsuitable for XFEL measurement.

Note: If your institution does not have access to pXRD, we have a partnership with the mail-in powder X-ray diffraction program (BL2-1) at the Stanford Synchrotron Radiation Light source (see link below). If you are interested in this as an alternative please check the appropriate box in your UPS submission. If electing to use SSRL for pXRD data, you still need to have this completed before the feasibility/safety review deadline one month prior to the start of beamtime.

https://web.slac.stanford.edu/stonegroup/PXRD

Hazardous Material Safety

Once their UPS submission has been accepted, users will need to provide safety documents which include a complete sample list spreadsheet (download template below) and safety data sheets (SDS) of the precursors and any known hazards for each sample. To protect our staff, a conservative Threshold Limit Value (TLV) will be determined for each sample by our Environmental, Health, and Safety (EH&S)
personnel. TLV is determined by the elemental composition of each sample and is defined as the maximum average airborne concentration of a chemical that healthy adult workers can be exposed to daily over a working lifetime without adverse health effects.

Sample List Spreadsheet

Air Sensitive Samples

Currently, the fixed target sample delivery system we are using is only designed for samples that are somewhat air-sensitive. We can measure in a helium environment and the vacuum grease itself is an insulating layer from oxidative effects but we cannot offer a completely air-tight environment. If your samples are air-sensitive, we recommend testing under similar conditions they will be measured in at your home institution. Samples should be able to withstand at least one to two hours of air exposure.

Sample Priority Designation

Sample priority is determined by a combination of two factors. The scientific case presented in your UPS submission (as reflected in the aggregated proposal for that material class) is evaluated by an independent proposal review process (PRP) and then our internal feasibility/safety review determines the likelihood of success for each sample as described above. Due to the limited beamtime available each run, the samples with the strongest scientific cases will be prioritized first assuming they pass our feasibility/safety review process. For science cases ranked equally strong, the pXRD and optical/SEM microscopy will be used to triage the remainder of the samples based on the “likelihood of success” as defined by our estimated ability to obtain an initial rough structure solution from a complete dataset (~40000 crystal images) collected for the sample. Of course, we strive to collect a complete dataset for every sample submitted and we thus try to accept a conservative number of samples for each beamtime but in the event of a significant loss of beamtime due to external factors, samples not measured at their designated beamtime will have higher priority during the next call.

Mail-in SFX Sample Preparation and Shipping Instructions

Following review, you will receive an email specifying which samples have been approved to participate in the program and feedback for the ones that cannot. Approved samples can then be shipped. See safety and feasibility section for specifics on sample approval.

Safety & Feasibility

Sample Preparation

To decrease the workload of LCLS staff scientists, we request that users adhere to our sample preparation and shipping guidelines as closely as possible. We recommend that users ship two vials of material for each sample if sufficient supply exists. One 20 mL wide mouth scintillation vial of premixed material (required, preparation below) and one vial of 10 mg dried powder as backup (optional). Samples are prepared by mixing the powders in Dow Corning high vacuum grease at a concentration of 20mg powder per gram of grease (use a minimum of 10 mg powder).

Note: Only this exact grease is currently approved for sample preparation.

If you do not have this grease or require something different for your individual samples for compatibility reasons please reach out to our team before preparing samples for shipping. Once mixed thoroughly, put mixture in a 20 mL wide mouth scintillation vial for shipping as shown below. Please label each vial with the minimum following information:

  • Element composition: AgSC3H6NO2
  • Weight dried powder: 10 mg

Note: Due to safety concerns samples without this label cannot be opened and must be disposed of as hazardous waste.

Once properly labeled, please seal each vial with a couple layers of parafilm to prepare for shipping and label them outside once again so that our staff can see the information easily. Please see Figure 4 for an example of sample preparation for shipping.

Examples of sample preparation for shipping
Figure 4: Examples of sample preparation for shipping.

Shipping Instructions

Prior to shipping samples, users will have already submitted safety information about each of their samples for approval from LCLS EH&S personnel including chemical formula or chemical composition of each material and safety data sheets (SDS) of the precursors and any known hazards for each sample. A printed copy of these SDS documents, a copy of the sample safety spreadsheet (see below), and any other handling information should be included in the shipping container to ensure the safety of those who receive it.

Sample List Spreadsheet

Note: We recommend packaging the samples properly to avoid damaging contents as packages suspected of containing opened or cracked vials may not be able to be opened and must be disposed of as hazardous waste.

Once properly packaged please ship to the following address:

Kelsey Banta, LCLS, MFX
SLAC National Accelerator Laboratory
2575 Sand Hill Rd., Bldg. #750
Menlo Park, CA 94025

Once shipped please forward any tracking information you have so that we can monitor the delivery and quickly store the contents once they arrive.

Contacts

Acknowledgements and Citations

Use of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515.

  1. Schriber, E. A.; Paley, D. W.; Bolotovsky, R.; Rosenberg, D. J.; Sierra, R. G.; Aquila, A.; Mendez, D.; Poitevin, F.; Blaschke, J. P.; Bhowmick, A.; Kelly, R. P.; Hunter, M.; Hayes, B.; Popple, D. C.; Yeung, M.; Pareja-Rivera, C.; Lisova, S.; Tono, K.; Sugahara, M.; Owada, S.; Kuykendall, T.; Yao, K.; Schuck, P. J.; Solis-Ibarra, D.; Sauter, N. K.; Brewster, A. S.; Hohman, J. N. Chemical Crystallography by Serial Femtosecond X-Ray Diffraction. Nature 2022, 601 (7893), 360–365. https://doi.org/10.1038/s41586-021-04218-3
  2. Brewster, A. S.; Sawaya, M. R.; Rodriguez, J.; Hattne, J.; Echols, N.; McFarlane, H. T.; Cascio, D.; Adams, P. D.; Eisenberg, D. S.; Sauter, N. K. Indexing Amyloid Peptide Diffraction from Serial Femtosecond Crystallography: New Algorithms for Sparse Patterns. Acta Cryst D 2015, 71 (2), 357–366. https://doi.org/10.1107/S1399004714026145

Pilot Program Contact Information

For general information regarding the program and submission of supporting documents:

For shipping information and to provide package tracking: