Coupling realistic pulsed beam temporal structures (micro/macro-pulses) with molecularDNA for DNA damage scoring and RBE estimation

Getting Started
1

Hello Geant4-DNA community,

I am a PhD student working on proton FLASH radiobiology using a laboratory cyclotron that delivers ultra-high dose rate beams with a complex temporal structure (micro-pulses on the ns scale and macro-pulses on the µs–ms scale). My goal is to simulate DNA damage (SSB, DSB, complex DSB) in a full cell nucleus under realistic FLASH temporal structures, and ultimately to estimate RBE.

I am using Geant4 11.4 on a Ubuntu

Geant4 Version: 11.4.2
Operating System: Ubuntu 24.04 LTS
Compiler/Version: g++ 11.4.0

Background

I previously attempted to link IRT-based pulse chemistry (TsIRTInterPulse) to SBS-based DNA damage scoring in a full nucleus geometry (TsNucleus + DNADamageNucleusStepByStep) within TOPAS-nBio 4.1.0. After discussion with the TOPAS-nBio maintainers, I was advised to look into the Geant4-DNA molecularDNA example and its associated publications as the appropriate framework for this type of coupling.

What I have found so far

From the molecularDNA documentation, I understand that:

  • The molecularDNA example uses a fractal nucleus geometry (continuous Hilbert curve, ~6.4 Gbp) with full DNA target representation, compatible with both direct and indirect DNA damage scoring.

  • The chemistry stage supports SBS, IRT, and a synchronous hybrid version (IRT-sync). The IRT-sync method computes the next reaction time using IRT, then explicitly diffuses all species for that time step and recalculates reaction times, thereby preserving spatio-temporal information on radicals required for combination with DNA geometries.

  • The UHDR example (Geant4 11.2+) provides a mesoscopic approach to study ROS production under different dose rate conditions, with multi-pulse simulation capability via pulseFile, multiPulse, pulsePeriod, and numberOfPulse.

My specific questions

  1. Can IRT-sync in molecularDNA accept a time-dependent sequence of pulses, or is it limited to a single instantaneous injection of chemical species? I need to inject primary species at multiple discrete times corresponding to my cyclotron’s micro-pulse and macro-pulse structure (e.g., ns-scale micro-pulses separated by ~40 ns, grouped into µs-scale macro-pulses with ms-scale inter-macro-pulse intervals). If IRT-sync cannot natively handle this, is there a recommended workaround (e.g., running multiple IRT-sync runs and merging radical populations at specified times)?

  2. Is the UHDR example’s pulse structure compatible with molecularDNA’s DNA scoring? The UHDR example uses a mesoscopic (SBS-RDME) approach with voxelized geometry, while molecularDNA uses a fractal DNA geometry. Can these two workflows be combined, or would I need to implement pulse-resolved chemistry directly within the molecularDNA framework?

  3. What is the appropriate level of temporal fidelity for my beam structure? My cyclotron produces micro-pulses (ns width, ~40 ns spacing) embedded in macro-pulses (µs width, ms spacing). The micro-pulse spacing is comparable to the chemical stage time scale (1 ps–1 µs). Should I treat the micro-pulse train as a continuous injection over the macro-pulse duration, or should I resolve individual micro-pulses? Is there a reference or benchmark I can use to validate this choice?

  4. Are there existing published methodological references or example configurations that couple pulsed radiation chemistry with DNA damage scoring in molecularDNA? I found the recent step-by-step Geant4-DNA framework for UHDR radio-induced chemistry using fluence-based dose modeling (Weishaar et al., Radiat. Phys. Chem., 2026), which implements pulse-resolved SBS chemistry. Would this framework be compatible with molecularDNA’s DNA geometry, or is it a separate implementation?

  5. As a longer-term goal, I ultimately need to map DNA damage yields to RBE. Are there any recommended models or published references for converting SSB/DSB yields (from molecularDNA or similar frameworks) into cell survival or RBE, particularly for proton FLASH conditions? I understand this likely requires a separate repair/survival model, but any pointers to established approaches would be very helpful.

Any guidance on which example or reference to start from would be greatly appreciated. I am happy to share my parameter files or further details if that helps.

Thank you very much for your time and support.

Best regards,
Chuanye Liu

2

I noticed that the Advanced Examples Working Plan for 2026 includes the item: “Improving pulse-structure implementation under UHDR conditions for the moleculardna example (2)” — scheduled for the second semester of 2026.

Could you please clarify the following:

  1. Implementation scope: Will this development allow the IRT-sync chemistry model in molecularDNA to accept a time-dependent sequence of chemical species injections (i.e., multiple discrete injection times corresponding to micro-pulses and macro-pulses), rather than being limited to a single instantaneous injection at t = 0?

  2. Input format: Will users be able to define the pulse structure through a macro command or input file (similar to the UHDR example’s pulseFile / multiPulse / pulsePeriod mechanism), or will it require custom C++ modifications?

  3. Compatibility with DNA scoring: Since molecularDNA uses a fractal DNA geometry (continuous Hilbert curve) while the UHDR example uses a mesoscopic voxelized geometry, will the new pulse-structure feature be implemented directly within the molecularDNA framework — thereby preserving compatibility with its DNA damage scoring (SSB, DSB, complex DSB) and radical-geometry interaction — or will it rely on an external coupling with the UHDR mesoscopic model?

  4. Release timeline: Is there an estimated release version (e.g., Geant4 11.5, 12.0) or a development branch that users can access to test this feature before the official release?

For reference, my beam structure consists of ns-scale micro-pulses separated by ~40 ns, grouped into µs-scale macro-pulses with ms-scale inter-macro-pulse intervals. The micro-pulse spacing is comparable to the chemical stage time scale (1 ps–1 µs), so the temporal fidelity of the injection mechanism is critical for my application.

I also came across the recent work by Weishaar et al. (Radiat. Phys. Chem., 2026) on a step-by-step Geant4-DNA framework for UHDR radio-induced chemistry using fluence-based dose modeling. Would this framework be compatible with molecularDNA’s DNA damage scoring, or is it intended as a standalone chemistry model?

Any information on the development status would be greatly appreciated. Thank you.

3

Dear,

Basically, IRT-syn is used in both UHDR and molecularDNA examples. Technically, you can apply the beam parameters from UHDR to molecularDNA. The problem is how to do chemistry in the cell nucleus up to the end of time structure and what can validate it ? Some ideas have been studied, but it is difficult to say whether the implementation will be released this year or next year.

4

Thank you very much for your clarification.
I understand that coupling realistic pulse structures with molecularDNA is still an active development area.

Since I mainly want to use the existing Geant4-DNA tools for my study, I would like to ask:

  1. For a proton cyclotron beam with ns-scale micro-pulses and µs-scale macro-pulses, is it currently practical to apply the UHDR pulse structure to the molecularDNA example for DNA damage scoring, or should some simplifications be considered?
  2. If a fully coupled pulse-chemistry-DNA simulation is not yet available, what would you recommend as a practical approach using the current Geant4-DNA examples?

Thank you again for your guidance.