PATHWAYS OF SCIENTIFIC DISCOVERY COMPUTER GENERATED MODELS CONTENTS Visualising A Cell : The Four Levels Of Protein Structure Protein Folding Symbolic Models: Bead Diagram Space-ﬁlling Model Ribbon Diagram Zig Zag Diagram CONCLUSION The impact of computers and the standardized symbolic representations used in microbiology. This section is designed to explain the most common diagrammatic representations used in molecular biology. However, to understand these diagrams, it is necessary to understand something about the structure of proteins and the process of folding. Primary structure The primary structure of a protein is the order of the amino acids, which are joined end to end. The primary structure of a protein is like a chain of varied beads; the chain can be made up of 20 different “beads.” This can be shown in a bead diagram. Each amino acid has a different side chain and these are distributed along this basic chain or backbone. It is the side-groups which cause the chain to be coiled into helices or folded into pleats to produce a stable functioning structure. Visualising a cell It is relatively easy to draw up a list of the constituents of a cell, but many properties of the cell, such as its life cycle, or its function, emerge as distinct properties in their own right. If a scientist needs to ‘represent’ a cell in its totality, he would have to try to include several levels of information. In addition, a cell contains more than 50,000 different varieties of protein/ enzyme, so trying to discover how these substances work within a cell is very difﬁcult. The third issue here is that these proteins are described as having a 4 level structure and scientists must represent these different levels. Secondary Structure The secondary structure consists of these helices and sheets. The entire amino chain that forms the protein consists of connected segments of the secondary structure; some look like helical coils, others resemble pleated sheets i.e. lengths of amino acids alongside each other. Between helices and sheets there are loops and turns. The Four levels of Protein Structure: Proteins are basically linear chains but they must fold into an intricate three-dimensional structure that is unique to each protein to become fully functional. Proteins consist of a backbone or chain of amino acids with attached side chains. It is believed that the side chains affect the way the chain will fold and it is only when the chain is folded that the protein can do its job. So it is the side chains that make one polypeptide chain fold into an α helix of hair keratin and another set of side chains that enable another chain to fold into the ß sheets of silk.. In order to understand the details of protein function, we must understand protein structure. Tertiary Structure The tertiary structure is the overall 3D shape of the folded chain. This compact tertiary structure of the molecule, is its most stable form. It is described as “folded”. Quartenary structure Where the ﬁnal functional protein consists of more than one polypeptide chain (e.g. haemoglobin) then it has a quaternary structure. Not all proteins exhibit quartenary structure. Folding “Anyone who has ever struggled to fold a roadmap should have an extra measure of respect for protein molecules, which fold up all on their own and practically put themselves away in the glove box. Protein folding is so remarkably efﬁcient that it has been called a paradox.” Brian Hayes An important metaphor used in the representation of cellular activity is “folding”. When we think of “folding” we can visualize a tablecloth, a sheet or a deckchair. Each of these examples involves reducing the size of something and involves bringing one part of it into contact with another part. The term “folding” in the cellular sense is used to describe the process where the long string of amino acids (as represented in a ribbon diagram) changes into a more compact form. Protein folding is one of the great unsolved problems of molecular biology. While we can represent the protein before it folds and when it is folded, we do not yet know enough about the actual process of folding and the energy it releases as it folds. We don’t see long strands of amino acids changing from a random chain to a compact 3 D structure, but we do know that a protein is not functional as an enzyme until it is folded. powerful research tools in molecular biology. The raw data is fed into a computer and the scientist can choose from various different representational models to demonstrate his ideas. Which kind of diagram he chooses depends on what exactly he wants to explain. While the screen of the computer is 2D, the modeling programmes enable a 3D perception of the structure, using techniques such as rotation, shading, and stereoscopy. Users interact with the model by adding and subtracting elements or by zooming into speciﬁc details. However the shift to computer modelling did not take place overnight; even today physical models continue to be used. Symbolising molecules Molecular scientists developed a symbolic visual language consisting of several types of computergenerated diagrams necessary for visualising cellular function. Like music notation these diagrams can be read. The representations range from the complex, in which every atom of the structure is shown, to the simple space-ﬁlled model showing the surface of a molecule. Each of the different models can be coloured in many ways. In standard colouring each element is given a different colour; it is also common to show each type of secondary structure as a different colour. Bead Diagram: Bead diagrams are useful for showing amino acid sequence (order). Models Today, models are usually created as computer generated images, using programs which can generate a model from data. They show which atom is connected to which and by what bonds. The programs are very sophisticated and can handle very large molecules. They can accept input from x-ray diffraction and from the various electron microscopes. Today anyone can access the Protein Data Bank to see the structure of thousands of proteins; interactive molecular modelling programmes have become Space-ﬁlling model If a scientist wants to demonstrate the overall structure of a molecule she will probably choose a space-ﬁlling model. For example a space-ﬁlling model of ATP synthase will show the arrangement of its two major structural parts ( F1 and Fo) factors involved in energy transfer. So, in a ribbon diagram the protein is seen as a stylized structure with regions of secondary structure connected by bends or unfolded lengths. From the ribbon diagram we get both a picture of the overall shape of the protein/enzyme and also clariﬁcation of the relationship of subunits; the protein sections are seen as the scaffolding that support various assemblies. In the ribbon diagram metaphor, the protein sections take on a different identity from that seen in the space-ﬁlled diagram. In a space – ﬁlled model it will also be clearly seen that the F1 is a globular assembly of ﬁve different proteins. Co-factors - Zig zag Diagram But if we need to know how an enzyme structure makes space for the co-factors that are involved in the process of enzyme catalysis and how these co-factors are attached to the main structure, we need to look more closely at the immediate surroundings of the active site. We need a closeup view - in other words we need another set of representations of the same data - a different metaphor is used. The zig zag chain diagram is a close-up view, it represents a close up of portions of the amino acid ...again a space ﬁlling model or other type of representation can be added to clarify more information, The main point with this type of visual metaphor is that it highlights particular features of the enzyme and its connection to various co-factors. Ribbon Diagrams Ribbon diagrams are one of the most popular ways to represent protein structures. In these diagrams, much of the structure is stripped away; helices are represented by either coiled ribbons or by thick tubes, beta-sheets are represented by arrows and ‘random coils’ are represented by lines or thin tubes. A ribbon diagram emphasises both the general form of the protein and the arrangement of the various sections in space. In addition, it is possible to add other types of model to the ribbon diagram to add more information, for example, space ﬁlled molecules can be added to represent co- Finally All these different representations are based on the same set of data and on the same underlying model and assumptions about the data and, inevitably, highlighting one aspect involves hiding another. In the space ﬁlling model we see the overall shape and non-bonded contacts between atoms; but this model obscures the secondary and tertiary structures of the proteins and shows only the surface. So the second SYMBOLIC representation – the Ribbon Diagram gives us a better sense of how the components of the enzyme are arranged with respect to one another and how co-factors and reacting molecules are arranged. Finally, in the zig zag representation, the molecule structure is abstracted in a different way to reveal the speciﬁc amino acids along the chains that are closest to the co-factor and with which they react. None of these different models is a literal description because we do not , in general, actually have access to sensory data directly from these molecular phenomena. Instead we have data that we can interpret in terms of metaphors in an ‘as if’ sense, (‘as if it were folded’) and as already pointed out models of atomic level structures are based on multiple assumptions and simpliﬁcations. All these representations of the enzyme, map onto the same data. Each model calls attention to a distinct interpretation of the data. However, the scientist must remember that each model hides certain properties or components of the system under study.
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