Structural biology

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Structural biology, as defined by the Journal of Structural Biology, deals with structural analysis of living material (formed, composed of, and/or maintained and refined by living cells) at every level of organization. [1]

Contents

Early structural biologists throughout the 19th and early 20th centuries were primarily only able to study structures to the limit of the naked eye's visual acuity and through magnifying glasses and light microscopes. In the 20th century, a variety of experimental techniques were developed to examine the 3D structures of biological molecules. The most prominent techniques are X-ray crystallography, nuclear magnetic resonance, and electron microscopy. Through the discovery of X-rays and its applications to protein crystals, structural biology was revolutionized, as now scientists could obtain the three-dimensional structures of biological molecules in atomic detail. [2] Likewise, NMR spectroscopy allowed information about protein structure and dynamics to be obtained. [3] Finally, in the 21st century, electron microscopy also saw a drastic revolution with the development of more coherent electron sources, aberration correction for electron microscopes, and reconstruction software that enabled the successful implementation of high resolution cryo-electron microscopy, thereby permitting the study of individual proteins and molecular complexes in three-dimensions at angstrom resolution.

With the development of these three techniques, the field of structural biology expanded and also became a branch of molecular biology, biochemistry, and biophysics concerned with the molecular structure of biological macromolecules (especially proteins, made up of amino acids, RNA or DNA, made up of nucleotides, and membranes, made up of lipids), how they acquire the structures they have, and how alterations in their structures affect their function. [4] This subject is of great interest to biologists because macromolecules carry out most of the functions of cells, and it is only by coiling into specific three-dimensional shapes that they are able to perform these functions. This architecture, the "tertiary structure" of molecules, depends in a complicated way on each molecule's basic composition, or "primary structure." At lower resolutions, tools such as FIB-SEM tomography have allowed for greater understanding of cells and their organelles in 3-dimensions, and how each hierarchical level of various extracellular matrices contributes to function (for example in bone). In the past few years it has also become possible to predict highly accurate physical molecular models to complement the experimental study of biological structures. [5] Computational techniques such as molecular dynamics simulations can be used in conjunction with empirical structure determination strategies to extend and study protein structure, conformation and function. [6]

Hemoglobin, the oxygen transporting protein found in red blood cells Hemoglobin t-r state ani.gif
Hemoglobin, the oxygen transporting protein found in red blood cells
Examples of protein structures from the Protein Data Bank (PDB) Protein structure examples.png
Examples of protein structures from the Protein Data Bank (PDB)

History

In 1912 Max Von Laue directed X-rays at crystallized copper sulfate generating a diffraction pattern. [7] These experiments led to the development of X-ray crystallography, and its usage in exploring biological structures. [5] 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. [8]

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. [9] The first tertiary protein structure, that of myoglobin, was published in 1958 by John Kendrew. [10] During this time, modeling of protein structures was done using balsa wood or wire models. [11] With the invention of modeling software such as CCP4 in the late 1970s, [12] 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, [13] and the use of structural biology in assisting synthetic biology. [14]

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). [15]

In 1990, Richard Henderson produced the first three-dimensional, high resolution image of bacteriorhodopsin using cryogenic electron microscopy (cryo-EM). [16] Since then, cryo-EM has emerged as an increasingly popular technique to determine three-dimensional, high resolution structures of biological images. [17]

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. [18] Recently, protein structure prediction was significantly improved by a new machine learning method called AlphaFold. [19] Some claim that computational approaches are starting to lead the field of structural biology research. [20]

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:

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

Flowchart of how structural biology plays a role in drug discovery Structural Biology and Drug Discovery.png
Flowchart of how structural biology plays a role in drug discovery

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. [21] 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. [22] 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. [23]

Structural biology is also an important component of drug discovery. [24] 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. [25] Similar research has been conducted for HIV targets to treat people with AIDS. [24] Researchers are also developing new antimicrobials for mycobacterial infections using structure-driven drug discovery. [24]

See also

Related Research Articles

<span class="mw-page-title-main">Crystallography</span> Scientific study of crystal structures

Crystallography is the branch of science devoted to the study of molecular and crystalline structure and properties. The word crystallography is derived from the Ancient Greek word κρύσταλλος, and γράφειν. In July 2012, the United Nations recognised the importance of the science of crystallography by proclaiming 2014 the International Year of Crystallography.

<span class="mw-page-title-main">X-ray crystallography</span> Technique used for determining crystal structures and identifying mineral compounds

X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract in specific directions. By measuring the angles and intensities of the X-ray diffraction, a crystallographer can produce a three-dimensional picture of the density of electrons within the crystal and the positions of the atoms, as well as their chemical bonds, crystallographic disorder, and other information.

The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules such as proteins and nucleic acids, which is overseen by the Worldwide Protein Data Bank (wwPDB). These structural data are obtained and deposited by biologists and biochemists worldwide through the use of experimental methodologies such as X-ray crystallography, NMR spectroscopy, and, increasingly, cryo-electron microscopy. All submitted data are reviewed by expert biocurators and, once approved, are made freely available on the Internet under the CC0 Public Domain Dedication. Global access to the data is provided by the websites of the wwPDB member organisations.

<span class="mw-page-title-main">John Kendrew</span> English biochemist and crystallographer

Sir John Cowdery Kendrew, was an English biochemist, crystallographer, and science administrator. Kendrew shared the 1962 Nobel Prize in Chemistry with Max Perutz, for their work at the Cavendish Laboratory to investigate the structure of haem-containing proteins.

<span class="mw-page-title-main">Transmission electron cryomicroscopy</span>

Transmission electron cryomicroscopy (CryoTEM), commonly known as cryo-EM, is a form of cryogenic electron microscopy, more specifically a type of transmission electron microscopy (TEM) where the sample is studied at cryogenic temperatures. Cryo-EM, specifically 3-dimensional electron microscopy (3DEM), is gaining popularity in structural biology.

<span class="mw-page-title-main">Cryogenic electron tomography</span>

Cryogenic electron tomography (cryoET) is an imaging technique used to reconstruct high-resolution (~1–4 nm) three-dimensional volumes of samples, often biological macromolecules and cells. cryoET is a specialized application of transmission electron cryomicroscopy (CryoTEM) in which samples are imaged as they are tilted, resulting in a series of 2D images that can be combined to produce a 3D reconstruction, similar to a CT scan of the human body. In contrast to other electron tomography techniques, samples are imaged under cryogenic conditions. For cellular material, the structure is immobilized in non-crystalline, vitreous ice, allowing them to be imaged without dehydration or chemical fixation, which would otherwise disrupt or distort biological structures.

Michael G. Rossmann was a German-American physicist, microbiologist, and Hanley Distinguished Professor of Biological Sciences at Purdue University who led a team of researchers to be the first to map the structure of a human common cold virus to an atomic level. He also discovered the Rossmann fold protein motif. His most well recognised contribution to structural biology is the development of a phasing technique named molecular replacement, which has led to about three quarters of depositions in the Protein Data Bank.

<span class="mw-page-title-main">Richard Henderson (biologist)</span> British biologist (born 1945)

Richard Henderson is a British molecular biologist and biophysicist and pioneer in the field of electron microscopy of biological molecules. Henderson shared the Nobel Prize in Chemistry in 2017 with Jacques Dubochet and Joachim Frank. "Thanks to his work, we can look at individual atoms of living nature, thanks to cryo-electron microscopes we can see details without destroying samples, and for this he won the Nobel Prize in Chemistry."

<span class="mw-page-title-main">Molecular biophysics</span> Interdisciplinary research area

Molecular biophysics is a rapidly evolving interdisciplinary area of research that combines concepts in physics, chemistry, engineering, mathematics and biology. It seeks to understand biomolecular systems and explain biological function in terms of molecular structure, structural organization, and dynamic behaviour at various levels of complexity. This discipline covers topics such as the measurement of molecular forces, molecular associations, allosteric interactions, Brownian motion, and cable theory. Additional areas of study can be found on Outline of Biophysics. The discipline has required development of specialized equipment and procedures capable of imaging and manipulating minute living structures, as well as novel experimental approaches.

Resolution in the context of structural biology is the ability to distinguish the presence or absence of atoms or groups of atoms in a biomolecular structure. Usually, the structure originates from methods such as X-ray crystallography, electron crystallography, or cryo-electron microscopy. The resolution is measured of the "map" of the structure produced from experiment, where an atomic model would then be fit into. Due to their different natures and interactions with matter, in X-ray methods the map produced is of the electron density of the system, whereas in electron methods the map is of the electrostatic potential of the system. In both cases, atomic positions are assumed similarly.

<span class="mw-page-title-main">Protein crystallization</span>

Protein crystallization is the process of formation of a regular array of individual protein molecules stabilized by crystal contacts. If the crystal is sufficiently ordered, it will diffract. Some proteins naturally form crystalline arrays, like aquaporin in the lens of the eye.

<span class="mw-page-title-main">Macromolecular assembly</span> Large chemical complexes composed of polymers and other macromolecules

In molecular biology, the term macromolecular assembly (MA) refers to massive chemical structures such as viruses and non-biologic nanoparticles, cellular organelles and membranes and ribosomes, etc. that are complex mixtures of polypeptide, polynucleotide, polysaccharide or other polymeric macromolecules. They are generally of more than one of these types, and the mixtures are defined spatially, and with regard to their underlying chemical composition and structure. Macromolecules are found in living and nonliving things, and are composed of many hundreds or thousands of atoms held together by covalent bonds; they are often characterized by repeating units. Assemblies of these can likewise be biologic or non-biologic, though the MA term is more commonly applied in biology, and the term supramolecular assembly is more often applied in non-biologic contexts. MAs of macromolecules are held in their defined forms by non-covalent intermolecular interactions, and can be in either non-repeating structures, or in repeating linear, circular, spiral, or other patterns. The process by which MAs are formed has been termed molecular self-assembly, a term especially applied in non-biologic contexts. A wide variety of physical/biophysical, chemical/biochemical, and computational methods exist for the study of MA; given the scale of MAs, efforts to elaborate their composition and structure and discern mechanisms underlying their functions are at the forefront of modern structure science.

<span class="mw-page-title-main">Structure validation</span> Process of evaluating 3-dimensional atomic models of biomacromolecules

Macromolecular structure validation is the process of evaluating reliability for 3-dimensional atomic models of large biological molecules such as proteins and nucleic acids. These models, which provide 3D coordinates for each atom in the molecule, come from structural biology experiments such as x-ray crystallography or nuclear magnetic resonance (NMR). The validation has three aspects: 1) checking on the validity of the thousands to millions of measurements in the experiment; 2) checking how consistent the atomic model is with those experimental data; and 3) checking consistency of the model with known physical and chemical properties.

Structural chemistry is a part of chemistry and deals with spatial structures of molecules and solids. For structure elucidation a range of different methods is used. One has to distinguish between methods that elucidate solely the connectivity between atoms (constitution) and such that provide precise three dimensional information such as atom coordinates, bond lengths and angles and torsional angles.

<span class="mw-page-title-main">Cryogenic electron microscopy</span> Form of transmission electron microscopy (TEM)

Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample solution is applied to a grid-mesh and plunge-frozen in liquid ethane or a mixture of liquid ethane and propane. While development of the technique began in the 1970s, recent advances in detector technology and software algorithms have allowed for the determination of biomolecular structures at near-atomic resolution. This has attracted wide attention to the approach as an alternative to X-ray crystallography or NMR spectroscopy for macromolecular structure determination without the need for crystallization.

<span class="mw-page-title-main">Tamir Gonen</span> American biochemist and biophysicist

Tamir Gonen is an American structural biochemist and membrane biophysicist best known for his contributions to structural biology of membrane proteins, membrane biochemistry and electron cryo-microscopy (cryoEM) particularly in electron crystallography of 2D crystals and for the development of 3D electron crystallography from microscopic crystals known as MicroED. Gonen is an Investigator of the Howard Hughes Medical Institute, a professor at the University of California, Los Angeles, the founding director of the MicroED Imaging Center at UCLA and a Member of the Royal Society of New Zealand.

Microcrystal electron diffraction, or MicroED, is a CryoEM method that was developed by the Gonen laboratory in late 2013 at the Janelia Research Campus of the Howard Hughes Medical Institute. MicroED is a form of electron crystallography where thin 3D crystals are used for structure determination by electron diffraction. Prior to this demonstration, macromolecular (protein) electron crystallography was mainly used on 2D crystals, for example. The method is one of several modern versions of approaches to determine atomic structures using electron diffraction first demonstrated for the positions of hydrogen atoms in NH4Cl crystals by W. E. Laschkarew and I. D. Usykin in 1933, which has since been used for surfaces, via precession electron diffraction, with much of the early work described in the work of Boris Vainshtein and Douglas L. Dorset.

This is a timeline of crystallography.

<span class="mw-page-title-main">Virus crystallisation</span> Re-arrangement of viral components into solid crystal particles

Virus crystallisation is the re-arrangement of viral components into solid crystal particles. The crystals are composed of thousands of inactive forms of a particular virus arranged in the shape of a prism. The inactive nature of virus crystals provide advantages for immunologists to effectively analyze the structure and function behind viruses. Understanding of such characteristics have been enhanced thanks to the enhancement and diversity in crystallisation technologies. Virus crystals have a deep history of being widely applied in epidemiology and virology, and still to this day remains a catalyst for studying viral patterns to mitigate potential disease outbreaks.

References

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  5. 1 2 Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ; Žídek, Augustin; Potapenko, Anna; Bridgland, Alex; Meyer, Clemens; Kohl, Simon A. A.; Ballard, Andrew J.; Cowie, Andrew (2021-07-15). "Highly accurate protein structure prediction with AlphaFold". Nature. 596 (7873): 583–589. Bibcode:2021Natur.596..583J. doi:10.1038/s41586-021-03819-2. ISSN   1476-4687. PMC   8371605 . PMID   34265844.
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