BilboMD: A web-accessible SAXS and AlphaFold-guided modeling pipeline
1. BilboMD is a free, no-login web platform for integrative modeling of flexible macromolecules using experimental SAXS/SANS plus atomistic starting models (experimental structures or AI predictions), aiming to make ensemble-based solution modeling accessible and reproducible.
2. A key innovation is automated definition of rigid vs flexible regions from AlphaFold confidence outputs: the PAE Jiffy converts AlphaFold PAE matrices (plus pLDDT) into CHARMM-compatible constraints, using Leiden clustering on a residue-residue similarity graph, then outputs a deterministic const.inp users can review and tweak.
3. BilboMD couples constrained conformational sampling (MD) with scattering-profile fitting: it generates many conformers, computes theoretical SAXS curves with FoXS, and selects best single- and multi-state ensembles with MultiFoXS—explicitly targeting systems where multiple conformations coexist in solution.
4. The pipeline uses a reduced MD representation: rigid domains are treated as frozen bodies while flexible linkers/regions are simulated, dramatically shrinking degrees of freedom so more conformational space can be explored for SAXS-consistent ensembles.
5. BilboMD automatically derives SAXS-driven radius-of-gyration restraints via a comprehensive Guinier scan across q-windows (with validation criteria like R² thresholds and qRg bounds), then biases MD sampling with harmonic restraints centered on the experimental Rg.
6. GPU acceleration is a major practical advance: an OpenMM-based variant (deployed on NERSC) delivers large speedups over CPU-based CHARMM for the MD step (reported 18×, 31×, and 78× on test systems), enabling larger conformer pools and more extensive ensemble fitting in feasible wall time.
7. Usability features target non-specialists while supporting power users: browser-based job submission with validation and sensible defaults, interactive Inp Jiffy for manual constraint authoring, results pages with before/after fits, residuals, downloadable bundles, and embedded Mol* visualization; API access supports automation and workflow integration.
8. BilboMD includes a diagnostic “feedback report” that goes beyond a final χ²: it estimates an appropriate ensemble state count (stopping when χ² improvement is no longer meaningful), checks molecular weight consistency (Vc-based MW) to flag aggregation/oligomer mismatch, and interprets fit failures by q-range to suggest concrete constraint edits.
9. Case studies illustrate typical outcomes: (i) Staphylococcal Eap required a 2-state ensemble to fit SAXS well (χ² improved from ~1.94 to ~1.17), reflecting domain flexibility; (ii) a PP1/PTG complex achieved a strong 2-state fit (χ² ~0.98); (iii) an aggregated sample was correctly diagnosed as not fixable by modeling because SAXS MW indicated major aggregation.
💻Code:
github.com/bl1231/bilbomd
📜Paper:
doi.org/10.1093/nar/gkag377
#SAXS #SANS #IntegrativeStructuralBiology #AlphaFold #MolecularDynamics #OpenMM #FoXS #EnsembleModeling #WebServer #ReproducibleResearch #HPC #GPUComputing