Structural biology

In 1912 Max Von Laue directed X-rays at crystallized copper sulfate generating a diffraction pattern. These experiments led to the development of X-ray crystallography, and its usage in exploring biological structures. In 1951, Rosalind Franklin and Maurice Wilkins used X-ray diffraction patterns to capture the first image of deoxyribonucleic acid (DNA). Francis Crick and James Watson modeled the double helical structure of DNA using this same technique in 1953 and received the Nobel Prize in Medicine along with Wilkins in 1962. Pepsin crystals were the first proteins to be crystallized for use in X-ray diffraction, by Theodore Svedberg who received the 1962 Nobel Prize in Chemistry. The first tertiary protein structure, that of myoglobin, was published in 1958 by John Kendrew. During this time, modeling of protein structures was done using balsa wood or wire models. With the invention of modeling software such as CCP4 in the late 1970s, modeling is now done with computer assistance. Recent developments in the field have included the generation of X-ray free electron lasers, allowing analysis of the dynamics and motion of biological molecules, and the use of structural biology in assisting synthetic biology. In the late 1930s and early 1940s, the combination of work done by Isidor Rabi, Felix Bloch, and Edward Mills Purcell led to the development of nuclear magnetic resonance (NMR). Currently, solid-state NMR is widely used in the field of structural biology to determine the structure and dynamic nature of proteins (protein NMR). In 1990, Richard Henderson produced the first three-dimensional, high resolution image of bacteriorhodopsin using cryogenic electron microscopy (cryo-EM). Since then, cryo-EM has emerged as an increasingly popular technique to determine three-dimensional, high resolution structures of biological images. More recently, computational methods have been developed to model and study biological structures. For example, molecular dynamics (MD) is commonly used to analyze the dynamic movements of biological molecules. In 1975, the first simulation of a biological folding process using MD was published in Nature. Recently, protein structure prediction was significantly improved by a new machine learning method called AlphaFold. Some claim that computational approaches are starting to lead the field of structural biology research. == Techniques ==

Biomolecules are too small to see in detail even with the most advanced light microscopes. The methods that structural biologists use to determine their structures generally involve measurements on vast numbers of identical molecules at the same time. These methods include: • Mass spectrometry • Macromolecular crystallography • Neutron diffraction • Proteolysis • Nuclear magnetic resonance spectroscopy of proteins (NMR) • Electron paramagnetic resonance (EPR) • Cryogenic electron microscopy (cryoEM) • Electron crystallography and microcrystal electron diffraction • Multiangle light scattering • Small angle scattering • Ultrafast laser spectroscopy • Anisotropic terahertz microspectroscopy • Two-dimensional infrared spectroscopy • Dual-polarization interferometry and circular dichroism Most often researchers use them to study the "native states" of macromolecules. But variations on these methods are also used to watch nascent or denatured molecules assume or reassume their native states. See protein folding. A third approach that structural biologists take to understanding structure is bioinformatics to look for patterns among the diverse sequences that give rise to particular shapes. Researchers often can deduce aspects of the structure of integral membrane proteins based on the membrane topology predicted by hydrophobicity analysis. See protein structure prediction. == Applications ==

Structural biologists have made significant contributions towards understanding the molecular components and mechanisms underlying human diseases. For example, cryo-EM and ssNMR have been used to study the aggregation of amyloid fibrils, which are associated with Alzheimer's disease, Parkinson's disease, and type II diabetes. In addition to amyloid proteins, scientists have used cryo-EM to produce high resolution models of tau filaments in the brain of Alzheimer's patients which may help develop better treatments in the future. Structural biology tools can also be used to explain interactions between pathogens and hosts. For example, structural biology tools have enabled virologists to understand how the HIV envelope allows the virus to evade human immune responses. Structural biology is also an important component of drug discovery. Scientists can identify targets using genomics, study those targets using structural biology, and develop drugs that are suited for those targets. Specifically, ligand-NMR, mass spectrometry, and X-ray crystallography are commonly used techniques in the drug discovery process. For example, researchers have used structural biology to better understand Met, a protein encoded by a protooncogene that is an important drug target in cancer. Similar research has been conducted for HIV targets to treat people with AIDS. Researchers are also developing new antimicrobials for mycobacterial infections using structure-driven drug discovery. == See also ==