Structural biology

Structural biology is the branch of the life sciences concerned with analysing the structure of living material at every level of organisation, from atoms and molecules to cells, tissues and complex biological assemblies. Because the function of biological macromolecules and systems is intimately linked to their three-dimensional architecture, structural biology seeks to understand how these structures are formed, maintained and altered, and how such changes influence biological activity.
During the nineteenth and early twentieth centuries, structural investigation was limited to what could be observed with the naked eye or with early optical instruments. The twentieth century brought a dramatic expansion of the field with the advent of techniques capable of probing macromolecules at atomic resolution. The development of X-ray crystallography, nuclear magnetic resonance spectroscopy and electron microscopy transformed biological research and laid the foundations of modern structural biology.

Background and scope

Structural biology concerns itself particularly with the architecture of biological macromolecules such as proteins, nucleic acids and lipid assemblies. These molecules perform the majority of cellular functions, from catalysis and signalling to structural support and transport. Their activity depends upon their ability to fold into precise three-dimensional conformations, with tertiary and quaternary structures governed by interactions within and between molecules. Understanding these structures is therefore essential for interpreting biological mechanisms.
As structural techniques improved, the field became deeply integrated with molecular biology, biochemistry and biophysics. Lower-resolution tools such as focused ion beam–scanning electron microscopy tomography have expanded the field to the study of whole cells and tissues in three dimensions, revealing how hierarchical structural organisation supports biological function—such as the architecture of bone and other extracellular matrices. More recently, computational approaches including molecular dynamics simulations and highly accurate predictive models have emerged to complement experimental determination.

Historical development

The modern era of structural biology began in 1912, when X-rays were first directed at crystalline materials to generate diffraction patterns. This innovation led to the establishment of X-ray crystallography as a powerful tool for determining molecular structure. By the early 1950s, X-ray diffraction was used to investigate the structure of DNA, providing key evidence for the double-helical model. Proteins soon followed: myoglobin became the first protein with a published tertiary structure in 1958, marking a major milestone in biological research.
Early models of protein structures were constructed physically using wooden or metal frameworks, but by the late 1970s computer-assisted modelling began to dominate. Over subsequent decades, new experimental tools emerged. Free-electron lasers allowed researchers to observe molecular dynamics on extremely short timescales, and advances in synthetic biology created new opportunities to design biological structures.
Nuclear magnetic resonance spectroscopy, rooted in discoveries from the 1930s and 1940s, developed into a major method for determining structures of proteins in solution. Solid-state NMR has since expanded its application to membrane proteins and large complexes. Electron microscopy likewise experienced a revolution: in 1990 the first high-resolution cryogenic electron microscopy (cryo-EM) structure was produced, and subsequent technological advances—improved electron sources, aberration correction and sophisticated reconstruction algorithms—elevated cryo-EM to a central role in modern structural biology.
Computational techniques have also accelerated rapidly. Molecular dynamics simulations began to reveal folding and conformational changes by the mid-1970s. More recently, machine-learning-based prediction methods have generated highly accurate models of protein structures, representing a significant advance in the field.

Techniques

Biomolecules are too small to visualise in detail with optical microscopy alone. Structural biologists therefore rely on methods that measure vast numbers of identical molecules to derive average structural information. Key approaches include:

• X-ray crystallography for atomic-resolution structures of crystallised molecules.
• Nuclear magnetic resonance spectroscopy for investigating structures and dynamics in solution or solid state.
• Electron microscopy, including cryo-EM and microcrystal electron diffraction, for high-resolution three-dimensional imaging of single particles and complexes.
• Electron paramagnetic resonance for probing distance constraints in paramagnetic systems.
• Circular dichroism and dual-polarisation interferometry for analysing secondary structures and conformational changes.

Alongside these experimental methods, bioinformatics is used to identify structural patterns within DNA or protein sequences, enabling researchers to infer membrane topology, predict structural motifs and model integral membrane proteins. Protein-folding studies often integrate both experimental and computational approaches to explore how unfolded or denatured molecules regain their native structures.

Applications

Structural biology plays an essential role in understanding human disease. High-resolution studies using cryo-EM and solid-state NMR have elucidated the structures of amyloid fibrils associated with Alzheimer’s disease, Parkinson’s disease and type 2 diabetes. Structural analysis of tau filaments has provided insight into neurodegenerative pathology and may guide the development of improved treatments.
In virology, structural methods have revealed how viral proteins, such as the HIV envelope, enable pathogens to evade immune responses and infect host cells. This knowledge has informed vaccine design and antiviral strategies.
Structural biology is also central to drug discovery. Genomic tools help identify potential drug targets, which can then be examined structurally to determine how ligands bind and to design molecules that alter target function. Nuclear magnetic resonance, mass spectrometry and X-ray crystallography are widely used to characterise ligand–target interactions. Structural analysis has supported drug development for cancer targets such as C-Met, as well as therapies for HIV and antimicrobials for mycobacterial infections.