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Molecular graphics is the discipline and philosophy of studying molecules and their properties through graphical representation. [1] IUPAC limits the definition to representations on a "graphical display device". [2] Ever since Dalton's atoms and Kekulé's benzene, there has been a rich history of hand-drawn atoms and molecules, and these representations have had an important influence on modern molecular graphics.
Colour molecular graphics are often used on chemistry journal covers artistically. [3]
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Prior to the use of computer graphics in representing molecular structure, Robert Corey and Linus Pauling developed a system for representing atoms or groups of atoms from hard wood on a scale of 1 inch = 1 angstrom connected by a clamping device to maintain the molecular configuration. [4] These early models also established the CPK coloring scheme that is still used today to differentiate the different types of atoms in molecular models (e.g. carbon = black, oxygen = red, nitrogen = blue, etc). This early model was improved upon in 1966 by W.L. Koltun and are now known as Corey-Pauling-Koltun (CPK) models. [5]
The earliest efforts to produce models of molecular structure was done by Project MAC using wire-frame models displayed on a cathode ray tube in the mid 1960s. In 1965, Carroll Johnson distributed the Oak Ridge thermal ellipsoid plot (ORTEP) that visualized molecules as a ball-and-stick model with lines representing the bonds between atoms and ellipsoids to represent the probability of thermal motion. [6] Thermal ellipsoid plots quickly became the de facto standard used in the display of X-ray crystallography data, and are still in wide use today. [6] The first practical use of molecular graphics was a simple display of the protein myoglobin using a wireframe representation in 1966 by Cyrus Levinthal and Robert Langridge working at Project MAC. [7]
Among the milestones in high-performance molecular graphics was the work of Nelson Max in "realistic" rendering of macromolecules using reflecting spheres.
Initially much of the technology concentrated on high-performance 3D graphics. [8] During the 1970s, methods for displaying 3D graphics using cathode ray tubes were developed using continuous tone computer graphics in combination with electro-optic shutter viewing devices. [9] The first devices used an active shutter 3D system, generating different perspective views for the left and right channel to provide the illusion of three-dimensional viewing. Stereoscopic viewing glasses were designed using lead lanthanum zirconate titanate (PLZT) ceramics as electronically-controlled shutter elements. [10] Active 3D glasses require batteries and work in concert with the display to actively change the presentation by the lenses to the wearer's eyes. Many modern 3D glasses use a passive, polarized 3D system that enables the wearer to visualize 3D effects based on their own perception. Passive 3D glasses are more common today since they are less expensive. [11]
The requirements of macromolecular crystallography also drove molecular graphics because the traditional techniques of physical model-building could not scale. The first two protein structures solved by molecular graphics without the aid of the Richards' Box were built with Stan Swanson's program FIT on the Vector General graphics display in the laboratory of Edgar Meyer at Texas A&M University: First Marge Legg in Al Cotton's lab at A&M solved a second, higher-resolution structure of staph. nuclease (1975) and then Jim Hogle solved the structure of monoclinic lysozyme in 1976. A full year passed before other graphics systems were used to replace the Richards' Box for modelling into density in 3-D. Alwyn Jones' FRODO program (and later "O") were developed to overlay the molecular electron density determined from X-ray crystallography and the hypothetical molecular structure.
Developer(s) | Approximate date | Technology | Comments |
---|---|---|---|
Crystallographers | < 1960 | Hand-drawn | Crystal structures, with hidden atom and bond removal. Often clinographic projections. |
Johnson, Motherwell | c. 1970 | Pen plotter | ORTEP, PLUTO. Very widely deployed for publishing crystal structures. |
Cyrus Levinthal, Bob Langridge, Ward, Stots [12] | 1966 | Project MAC display system, two-degree of freedom, spring-return velocity joystick for rotating the image. | First protein display on screen. System for interactively building protein structures. |
Barry [13] | 1969 | LINC 300 computer with a dual trace oscilloscope display. | Interactive molecular structure viewing system. Early examples of dynamic rotation, intensity depth·cueing, and side-by-side stereo. Early use of the small angle approximations (a = sin a, 1 = cos a) to speed up graphical rotation calculations. |
Ortony | 1971 | Designed a stereo viewer (British patent appl. 13844/70) for molecular computer graphics. | Horizontal two-way (half-silvered) mirror combines images drawn on the upper and lower halves of a CRT. Crossed polarizers isolate the images to each eye. |
Ortony [14] | 1971 | Light pen, knob. | Interactive molecular structure viewing system. Select bond by turning another knob until desired bond lights up in sequence, a technique later used on the MMS-4 system below, or by picking with the light pen. Points in space are specified with a 3-D ”bug" under dynamic control. |
Barry, Graesser, Marshall [15] | 1971 | CHEMAST: LINC 300 computer driving an oscilloscope. Two-axis joystick, similar to one used later by GRIP-75 (below). | Interactive molecular structure viewing system. Structures dynamically rotated using the joystick. |
Tountas and Katz [16] | 1971 | Adage AGT/50 display | Interactive molecular structure viewing system. Mathematics of nested rotation and for laboratory-space rotation. |
Perkins, Piper, Tattam, White [17] | 1971 | Honeywell DDP 516 computer, EAL TR48 analog computer, Lanelec oscilloscope, 7 linear potentiometers. Stereo. | Interactive molecular structure viewing system. |
Wright [18] [19] [20] | 1972 | GRIP-71 at UNC-CH: IBM System/360 Model 40 time-shared computer, IBM 2250 display, buttons, light pen, keyboard. | Discrete manipulation and energy relaxation of protein structures. Program code became the foundation of the GRIP-75 system below. |
Barry and North [21] | 1972 | University of Oxford: Ferranti Argus 500 computer, Ferranti model 30 display, keyboard, track ball, one knob. Stereo. | Prototype large-molecule crystallographic structure solution system. Track ball rotates a bond, knob brightens the molecule vs. electron density map. |
North, Ford, Watson | Early 1970s | University of Leeds: DEC PDP·11/40 computer, Hewlett-Packard display. 16 knobs, keyboard, spring-return joystick. Stereo. | Prototype large-molecule crystallographic structure solution system. Six knobs rotate and translate a small molecule. |
Barry, Bosshard, Ellis, Marshall, Fritch, Jacobi | 1974 | MMS-4: [22] [23] Washington University in St. Louis, LINC 300 computer and an LDS-1 / LINC 300 display, custom display modules. Rotation joystick, knobs. Stereo. | Prototype large-molecule crystallographic structure solution system. Select bond to rotate by turning another knob until desired bond lights up in sequence. |
Cohen and Feldmann [24] | 1974 | DEC PDP-10 computer, Adage display, push buttons, keyboard, knobs | Prototype large-molecule crystallographic structure solution system. |
Stellman [25] | 1975 | Princeton University: PDP-10 computer, LDS-1 display, knobs | Prototype large-molecule crystallographic structure solution system. Electron density map not shown; instead an "H Factor" figure of merit is updated as the molecular structure is manipulated. |
Collins, Cotton, Hazen, Meyer, Morimoto | 1975 | CRYSNET, [26] Texas A&M Univ. DEC PDP-11/40 computer, Vector General Series 3 display, knobs, keyboard. Stereo. | Prototype large-molecule crystallographic structure solution system. Variety of viewing modes: rocking, spinning, and several stereo display modes. |
Cornelius and Kraut | 1976 (approx.) | University of California at San Diego: DEC PDP-11/40 emulator (CalData 135), Evans and Sutherland Picture System display, keyboard, 6 knobs. Stereo. | Prototype large-molecule crystallographic structure solution system. |
(Yale Univ.) | 1976 (approx.) | PIGS: DEC PDP-11/70 computer, Evans and Sutherland Picture System 2 display, data tablet, knobs. | Prototype large-molecule crystallographic structure solution system. The tablet was used for most interactions. |
Feldmann and Porter | 1976 | NIH: DEC PDP—11/70 computer. Evans and Sutherland Picture System 2 display, knobs. Stereo. | Interactive molecular structure viewing system. Intended to display interactively molecular data from the AMSOM – Atlas of Macromolecular Structure on Microfiche. [27] |
Rosenberger et al. | 1976 | MMS-X: [28] Washington University in St. Louis, TI 980B computer, Hewlett-Packard 1321A display, Beehive video terminal, custom display modules, pair of 3-D spring-return joysticks, knobs. | Prototype (and later successful) large-molecule crystallographic structure solution system. Successor to the MMS-4 system above. The 3-D spring-return joysticks either translate and rotate the molecular structure for viewing or a molecular substructure for fitting, mode controlled by a toggle switch. |
Britton, Lipscomb, Pique, Wright, Brooks | 1977 | GRIP-75 [20] [29] [30] [31] [32] at UNC-CH: Time-shared IBM System/360 Model 75 computer, DEC PDP 11/45 computer, Vector General Series 3 display, 3-D movement box from A.M. Noll and 3-D spring return joystick for substructure manipulation, Measurement Systems nested joystick, knobs, sliders, buttons, keyboard, light pen. | First large-molecule crystallographic structure solution. [33] |
Jones | 1978 | FRODO and RING [34] [35] Max Planck Inst., Germany, RING: DEC PDP-11/40 and Siemens 4004 computers, Vector General 3404 display, 6 knobs. | Large-molecule crystallographic structure solution. FRODO may have run on a DEC VAX-780 as a follow-on to RING. |
Diamond | 1978 | Bilder [36] Cambridge, England, DEC PDP-11/50 computer, Evans and Sutherland Picture System display, tablet. | Large-molecule crystallographic structure solution. All input is by data tablet. Molecular structures built on-line with ideal geometry. Later passes stretch bonds with idealization. |
Langridge, White, Marshall | Late 1970s | Departmental systems (PDP-11, Tektronix displays or DEC-VT11, e.g. MMS-X) | Mixture of commodity computing with early displays. |
Davies, Hubbard | Mid-1980s | CHEM-X, HYDRA | Laboratory systems with multicolor, raster and vector devices (Sigmex, PS300). |
Biosym, Tripos, Polygen | Mid-1980s | PS300 and lower cost dumb terminals (VT200, SIGMEX) | Commercial integrated modelling and display packages. |
Silicon Graphics, Sun | Late 1980s | IRIS GL (UNIX) workstations | Commodity-priced single-user workstations with stereoscopic display. |
EMBL - WHAT IF | 1989, 2000 | Machine independent | Nearly free, multifunctional, still fully supported, many free servers based on it |
Sayle, Richardson | 1992, 1993 | RasMol, Kinemage | Platform-independent MG. |
MDL (van Vliet, Maffett, Adler, Holt) | 1995–1998 | Chime | proprietary C++; free browser plugin for Mac (OS9) and PCs |
MolSoft | 1997–present | ICM-Browser | proprietary; free download for Windows, Mac, and Linux. [37] [38] |
1998- | MarvinSketch & MarvinView. MarvinSpace (2005) | proprietary Java applet or stand-alone application. |
In the ball-and-stick model, atoms are drawn as small sphered connected by rods representing the chemical bonds between them.
In the space-filling model, atoms are drawn as solid spheres to suggest the space they occupy, in proportion to their van der Waals radii. Atoms that share a bond overlap with each other.
In some models, the surface of the molecule is approximated and shaded to represent a physical property of the molecule, such as electronic charge density. [39] [40]
Ribbon diagrams are schematic representations of protein structure and are one of the most common methods of protein depiction used today. The ribbon shows the overall path and organization of the protein backbone in 3D, and serves as a visual framework on which to hang details of the full atomic structure, such as the balls for the oxygen atoms bound to the active site of myoglobin in the adjacent image. Ribbon diagrams are generated by interpolating a smooth curve through the polypeptide backbone. α-helices are shown as coiled ribbons or thick tubes, β-strands as arrows, and non-repetitive coils or loops as lines or thin tubes. The direction of the polypeptide chain is shown locally by the arrows, and may be indicated overall by a colour ramp along the length of the ribbon. [41]
Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids. Crystallography is a fundamental subject in the fields of materials science and solid-state physics. 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 that 2014 would be the International Year of Crystallography.
Structural biology, as defined by the Journal of Structural Biology, deals with structural analysis of living material at every level of organization. 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.
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles and intensities of these diffracted beams, a crystallographer can produce a three-dimensional picture of the density of electrons within the crystal. From this electron density, the positions of the atoms in the crystal can be determined, as well as their chemical bonds, crystallographic disorder, and various 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. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, cryo-electron microscopy, and submitted by biologists and biochemists from around the world, are freely accessible on the Internet via the websites of its member organisations. The PDB is overseen by an organization called the Worldwide Protein Data Bank, wwPDB.
Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic "evolution" of the system. In the most common version, the trajectories of atoms and molecules are determined by numerically solving Newton's equations of motion for a system of interacting particles, where forces between the particles and their potential energies are often calculated using interatomic potentials or molecular mechanical force fields. The method is applied mostly in chemical physics, materials science, and biophysics.
Structural bioinformatics is the branch of bioinformatics that is related to the analysis and prediction of the three-dimensional structure of biological macromolecules such as proteins, RNA, and DNA. It deals with generalizations about macromolecular 3D structures such as comparisons of overall folds and local motifs, principles of molecular folding, evolution, binding interactions, and structure/function relationships, working both from experimentally solved structures and from computational models. The term structural has the same meaning as in structural biology, and structural bioinformatics can be seen as a part of computational structural biology. The main objective of structural bioinformatics is the creation of new methods of analysing and manipulating biological macromolecular data in order to solve problems in biology and generate new knowledge.
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In addition to small molecules, biopharmaceuticals including peptides and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also been developed.
A kinemage is an interactive graphic scientific illustration. It often is used to visualize molecules, especially proteins although it can also represent other types of 3-dimensional data. The kinemage system is designed to optimize ease of use, interactive performance, and the perception and communication of detailed 3D information. The kinemage information is stored in a text file, human- and machine-readable, that describes the hierarchy of display objects and their properties, and includes optional explanatory text. The kinemage format is a defined chemical MIME type of 'chemical/x-kinemage' with the file extension '.kin'.
In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using, for example, scoring functions.
Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and their complexes. The field was pioneered by Richard R. Ernst and Kurt Wüthrich at the ETH, and by Ad Bax, Marius Clore, Angela Gronenborn at the NIH, and Gerhard Wagner at Harvard University, among others. Structure determination by NMR spectroscopy usually consists of several phases, each using a separate set of highly specialized techniques. The sample is prepared, measurements are made, interpretive approaches are applied, and a structure is calculated and validated.
Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool, or for research e.g., in chemistry and biochemistry.
A molecular model is a physical model of an atomistic system that represents molecules and their processes. They play an important role in understanding chemistry and generating and testing hypotheses. The creation of mathematical models of molecular properties and behavior is referred to as molecular modeling, and their graphical depiction is referred to as molecular graphics.
BALL is a C++ class framework and set of algorithms and data structures for molecular modelling and computational structural bioinformatics, a Python interface to this library, and a graphical user interface to BALL, the molecule viewer BALLView.
Frederic Middlebrook Richards, commonly referred to as Fred Richards, was an American biochemist and biophysicist known for solving the pioneering crystal structure of the ribonuclease S enzyme in 1967 and for defining the concept of solvent-accessible surface. He contributed many key experimental and theoretical results and developed new methods, garnering over 20,000 journal citations in several quite distinct research areas. In addition to the protein crystallography and biochemistry of ribonuclease S, these included solvent accessibility and internal packing of proteins, the first side-chain rotamer library, high-pressure crystallography, new types of chemical tags such as biotin/avidin, the nuclear magnetic resonance (NMR) chemical shift index, and structural and biophysical characterization of the effects of mutations.
In chemistry, a space-filling model, also known as a calotte model, is a type of three-dimensional (3D) molecular model where the atoms are represented by spheres whose radii are proportional to the radii of the atoms and whose center-to-center distances are proportional to the distances between the atomic nuclei, all in the same scale. Atoms of different chemical elements are usually represented by spheres of different colors.
Jane Shelby Richardson is an American biophysicist best known for developing the Richardson diagram, or ribbon diagram, a method of representing the 3D structure of proteins. Ribbon diagrams have become a standard representation of protein structures that has facilitated further investigation of protein structure and function globally. With interests in astronomy, math, physics, botany, and philosophy, Richardson took an unconventional route to establishing a science career. Richardson is a professor in biochemistry at Duke University.
Ribbon diagrams, also known as Richardson diagrams, are 3D schematic representations of protein structure and are one of the most common methods of protein depiction used today. The ribbon depicts the general course and organisation of the protein backbone in 3D and serves as a visual framework for hanging details of the entire atomic structure, such as the balls for the oxygen atoms attached to myoglobin's active site in the adjacent figure. Ribbon diagrams are generated by interpolating a smooth curve through the polypeptide backbone. α-helices are shown as coiled ribbons or thick tubes, β-sheets as arrows, and non-repetitive coils or loops as lines or thin tubes. The direction of the polypeptide chain is shown locally by the arrows, and may be indicated overall by a colour ramp along the length of the ribbon.
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.
The program Coot is used to display and manipulate atomic models of macromolecules, typically of proteins or nucleic acids, using 3D computer graphics. It is primarily focused on building and validation of atomic models into three-dimensional electron density maps obtained by X-ray crystallography methods, although it has also been applied to data from electron microscopy.
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.