Cryo-EM has transformed structural biology by enabling atomic-resolution imaging of macromolecules without requiring crystallization. The method involves flash-freezing samples in vitreous ice and visualizing them under transmission electron microscopes. Advances in direct electron detectors and image reconstruction algorithms have made Cryo-EM a preferred modality for studying membrane proteins, large assemblies, and viral particles. Thermo Fisher Scientific is a leader in this space, offering flagship systems like the Titan Krios and Talos Arctica, known for automation and high-throughput capabilities. These instruments have become critical assets for core facilities and research consortia. Between 2018 and 2024, NIH’s Transformative High-Resolution Cryo-Electron Microscopy Program invested approximately $129.5 million to establish three national service centers and develop training curricula. In 2024, operations transitioned to the National Institute of General Medical Sciences, while the National Network for Cryo-Electron Tomography continues to expand through 2026. Though adoption has grown, the field remains dependent on centralized infrastructure, making it particularly vulnerable to financial uncertainty.
X-ray crystallography remains a foundational tool in structural biology, particularly in pharmaceutical research and protein engineering. The technique reconstructs atomic models from the diffraction patterns of X-rays passing through ordered crystals. While crystallization can pose challenges, crystallography offers unmatched resolution and is indispensable for small molecule and structure-based drug discovery. Suppliers such as Rigaku, Bruker, and Dectris have driven innovation. Rigaku’s XtaLAB Synergy and Bruker’s D8 VENTURE platforms integrate high-flux sources, photon-counting detectors, and automated sample handling. Dectris, a leader in hybrid photon-counting detector technology, supplies the widely used PILATUS and EIGER detector series. These detectors offer high frame rates, low noise, and large dynamic ranges, enabling time-resolved and high-throughput data collection that supports modern crystallographic workflows. Although direct NIH funding for crystallography has decreased, the technique remains supported through broader structural biology grants and instrumentation programs.
NMR spectroscopy provides unique capabilities for investigating molecular dynamics, conformational flexibility, and ligand binding. By measuring the magnetic properties of atomic nuclei in solution, NMR reveals both spatial and temporal aspects of biomolecules, making it especially effective for studying disordered proteins, folding intermediates, and chemical exchange processes. Major instrument providers include Bruker and JEOL. Bruker’s AVANCE NEO and JEOL’s ECZ Luminous systems offer high-field magnets, cryogenic probes, and advanced pulse sequences for multidimensional experiments. NIH has supported NMR through programs such as RM1 center grants and BTOD awards. Notable examples include the National Resource for Advanced NMR Technology (RM1-GM148766), which focuses on technological innovation and service to the broader community. However, NMR facilities often require continuous investment in hardware, software, and skilled personnel.
Although not a primary tool for structure determination, LC/MS is essential in structural biology for identifying proteins, mapping post-translational modifications, and studying protein–protein interactions. The technique is particularly powerful when coupled with hydrogen-deuterium exchange (HDX), cross-linking mass spectrometry, and other structural proteomics strategies. Key players include Thermo Fisher Scientific, Agilent Technologies, and Waters Corporation. Thermo Fisher’s Orbitrap series and Agilent’s 6545XT AdvanceBio systems are valued for high accuracy and reproducibility. Waters contributes significantly to structural biology through systems such as the SYNAPT G2-Si and SELECT SERIES Cyclic IMS. These platforms incorporate ion mobility separation and HDX-MS capabilities, allowing detailed analysis of conformational states and dynamic protein interactions.
AI is rapidly reshaping the structural biology landscape by automating data analysis and enhancing predictive modeling. Deep learning tools such as DeepPicker, crYOLO, and TOPAZ accelerate Cryo-EM workflows by improving particle detection and image reconstruction. AlphaFold, developed by DeepMind, has revolutionized access to predicted protein structures and is now routinely integrated into both Cryo-EM and crystallographic pipelines. Instrument vendors are also embedding AI into their platforms. Thermo Fisher’s CryoSPIN and Bruker’s TopSpin incorporate machine learning for spectral interpretation, structural modeling, and experimental optimization. Commercial service providers like Creative Biostructure and Nanomega CryoAI are offering AI-augmented services for drug discovery and structural analysis.
Across all modalities, NIH funding has been the engine behind U.S. leadership in structural biology. Targeted programs like the Common Fund initiative for Cryo-EM, RM1 center grants for NMR, and shared instrumentation grants for LC/MS have enabled research institutions to acquire and maintain sophisticated instrumentation, support training pipelines, and promote collaboration. However, recent NIH budget proposals reductions in research spending and caps on indirect cost recovery pose serious risks to the structural biology ecosystem. Core facilities and university laboratories could face untenable operating conditions, especially for high-capital modalities like Cryo-EM and NMR that depend on centralized infrastructure. Such reductions may delay innovation, shrink research capacity, and ultimately raise long-term healthcare costs by slowing translational research. Modality-specific risk assessments highlight Cryo-EM and AI as particularly exposed due to infrastructure needs and coordination complexity.
Technological progress in structural biology has given scientists powerful tools to decode the molecular basis of life, but fiscal volatility now threatens to erode hard-won gains. NIH investments in Cryo-EM, NMR, LC/MS, crystallography, and AI have catalyzed major scientific breakthroughs. Yet without strategic, stable funding, continued innovation is at risk. Sustaining the impact of structural biology will require adaptive strategies: diversified support from public and private sources, stronger partnerships between academia and industry, and more resilient funding models for infrastructure-intensive modalities.