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Molecular and Protein Interactive Figures - Biology

Molecular and Protein Interactive Figures - Biology


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Molecular and Protein Interactive Figures

7 Biodiversity

Figure 1. From left to right: Row 1: frogfish, moss, sea urchin, woodland crocus, and a flatworm Row 2: alien lizard, archean cell infected with a virus, monarch butterfly, and platypus Row 3: weevil, salmonella, hornbill, garden spider, and mushroom.
  • Define biodiversity.
  • Use visual models to characterize the scope of biodiversity on earth.
  • Describe efforts to conserve threatened and endangered species.
  • Explain the Red List of Threatened Species.
  • Recognize types of protected areas.
  • Describe the benefits of biodiversity.
  • Characterize the threats to biodiversity.
  • Explain ways in which organizations are working to save biodiversity.

Interactive learning modules with 3D printed models improve student understanding of protein structure–function relationships

Dr. Rebecca L. Roston, Department of Biochemistry, University of Nebraska, N123 Beadle Center, Lincoln, NE 68588-0664.

Dr. Brian A. Couch, School of Biological Sciences, University of Nebraska, 204 Manter Hall, Lincoln, NE 68588-0118.

LCC International University, Klaipėda, Lithuania

Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA

School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA

Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA

Department of Chemistry, Doane University, Crete, Nebraska, USA

Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA

Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA

Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA

School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA

Dr. Rebecca L. Roston, Department of Biochemistry, University of Nebraska, N123 Beadle Center, Lincoln, NE 68588-0664.

Dr. Brian A. Couch, School of Biological Sciences, University of Nebraska, 204 Manter Hall, Lincoln, NE 68588-0118.

Roston and Couch contributed equally to this manuscript.

Funding information: National Science Foundation, Grant/Award Number: DUE-1625804

Abstract

Ensuring undergraduate students become proficient in relating protein structure to biological function has important implications. With current two-dimensional (2D) methods of teaching, students frequently develop misconceptions, including that proteins contain a lot of empty space, that bond angles for different amino acids can rotate equally, and that product inhibition is equivalent to allostery. To help students translate 2D images to 3D molecules and assign biochemical meaning to physical structures, we designed three 3D learning modules consisting of interactive activities with 3D printed models for amino acids, proteins, and allosteric regulation with coordinating pre- and post-assessments. Module implementation resulted in normalized learning gains on module-based assessments of 30% compared to 17% in a no-module course and normalized learning gains on a comprehensive assessment of 19% compared to 3% in a no-module course. This suggests that interacting with these modules helps students develop an improved ability to visualize and retain molecular structure and function.

Supporting Information S1 Module 1: Amino acid structure and function—Activity

Supporting Information S2 Module 1: Amino acid structure and function—Slides

Supporting Information S3 Module 1: Amino acid structure and function—Assessment

Supporting Information S4 Module 2: Protein structure and function—Activity

Supporting Information S5 Module 2: Protein structure and function—Slides

Supporting Information S6 Module 2: Protein structure and function—Assessment

Supporting Information S7 Module 3: Allosteric enzyme regulation—Activity

Supporting Information S8 Module 3: Allosteric enzyme regulation—Slides

Supporting Information S9 Module 3: Allosteric enzyme regulation—Assessment

Supporting Information S10 How to obtain and prepare the 3D models for class use (FAQs)

Supporting Information S11 Survey of protein 3D model experience

Supporting Information S12 Structure and function course assessment

Supplemental Table 1 Class performance on the pre- and post-assessments for each 3D learning module.

Supplemental Table 2 Consenting class performance on learning objectives for the pre- and post-assessments for each 3D learning module.

Supplemental Figure S1. 3D learning modules benefit students regardless of gender. Normalized learning gains are plotted for males (red) and females (grey) (A) with intervention, and (B) without intervention. Fold difference is reported for female gains compared to male gains.

Supplemental Figure S2. 3D learning modules improve small-enrollment class performance on content assessments. Class performance on pre- and post-assessment items is plotted for (A) Assessment I: Amino acids, (B) II: Proteins, and (C) III: Allostery in small-format classes in which the modules were used.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.


Key Points

The availability of complete genome sequences for some organisms allows the prediction of complete sets of proteins — proteomes.

To characterize protein function on a genome-wide scale, functional genomic approaches are now being taken. These are usually based on conventional assays modified to allow high-throughput or automated settings in which many proteins can be analysed simultaneously.

One functional genomic approach consists of the systematic identification of physical protein–protein interactions for a given proteome, with the aim of generating comprehensive protein interaction maps.

In classical proteomic approaches, the starting material is a protein extract from the organism. Such approaches are often limited by their inability to identify specific interactions within a complex of interacting proteins. This limitation can potentially be overcome by reverse proteomic approaches.

In reverse proteomic approaches, which can be computer-based or experimental, experiments are designed using the predicted proteome.

Computer-based approaches can use three assumptions:

Proteins encoded by pairs of separate genes functionally interact if their orthologues (proteins that have similar functions in different organisms) are known to be part of a single protein in another organism.

There is strong selective pressure for functionally interacting proteins to be inherited together during speciation.

Proteins that physically interact in one organism will co-evolve so that their respective orthologues maintain the ability to interact in another organism.

The yeast two-hybrid approach allows yeast cells expressing an interacting protein pair (X and Y) to be selected by using fusion tags attached to X and Y that reconstitute a transcription factor upon an interaction between X and Y, leading to the activation of reporter gene expression. This approach can be used to systematically test many possible interacting pairs.

Potential interactions can be confirmed by co-purifying or co-immunoprecipitating the partner proteins, examining loss-of-function phenotypes of the genes that encode interaction partners, or examining the effect of a loss of a protein interaction in vivo.


Mechanisms of BCR-ABL–mediated malignant transformation

Essential features of the Bcr-Abl protein

Mutational analysis identified several features in the chimeric protein that are essential for cellular transformation (Figure4). In Abl they include the SH1, SH2, and actin-binding domains (Figure 1), and in Bcr they include a coiled–coil motif contained in amino acids 1-63,25 the tyrosine at position 177,57 and phosphoserine–threonine-rich sequences between amino acids 192-242 and 298-41358 (Figure 2). It is, however, important to note that essential features depend on the experimental system. For example, SH2 deletion mutants of Bcr-Abl are defective for fibroblast transformation,59 but they retain the capacity to transform cell lines to factor independence and are leukemogenic in animals.60

Signaling pathways activated in

BCR-ABL–positive cells. Note that this is a simplified diagram and that many more associations between Bcr-Abl and signaling proteins have been reported.

Signaling pathways activated in

BCR-ABL–positive cells. Note that this is a simplified diagram and that many more associations between Bcr-Abl and signaling proteins have been reported.

Deregulation of the Abl tyrosine kinase

Abl tyrosine kinase activity is tightly regulated under physiologic conditions. The SH3 domain appears to play a critical role in this inhibitory process because its deletion14 or positional alteration61 activates the kinase it is replaced by viral gag sequences in v-abl.62 Both cis- and trans-acting mechanisms have been proposed to mediate the repression of the kinase. Several proteins have been identified that bind to the SH3 domain.63-65 Abi-1 and Abi-2 (Abl interactor proteins 1 and 2) activate the inhibitory function of the SH3 domain even more interesting, activated Abl proteins promote the proteasome-mediated degradation of Abi-166 and Abi-2. Another candidate inhibitor of Abl is Pag/Msp23. On exposure of cells to oxidative stress such as ionizing radiation, this small protein is oxidized and dissociates from Abl, whose kinase is in turn activated.67These results are in line with previous observations that highly purified Abl protein is kinase-active,61 suggesting that its constitutive inhibition derives from a trans-acting mechanism. Alternatively, the SH3 domain may bind internally to the proline-rich region in the center of the Abl protein, causing a conformational change that inhibits interaction with substrates.68Furthermore, a mutation of Phe 401 to Val (within the kinase domain) leads to the transformation of rodent fibroblasts. Because this residue is highly conserved in tyrosine kinases with N-terminal SH3 domains, it may bind internally to the SH3 domain.69 It is conceivable that the fusion of Bcr sequences 5′ of the Abl SH3 domain abrogates the physiologic suppression of the kinase. This might be the consequence of homodimer formation indeed, the N-terminal dimerization domain is an essential feature of the Bcr-Abl protein but can be functionally replaced by other sequences that allow for dimer formation, such as the N-terminus of the TEL(ETV-6) transcription factor in the TEL-ABLfusion associated with the t(912).43,70 It is possible that deregulated tyrosine kinase activity is a unifying feature of chronic myeloproliferative disorders. Several other reciprocal translocations have been cloned from patients with chronicBCR-ABL–negative myeloproliferative disorders. Remarkably, most of these turn out to involve tyrosine kinases such as fibroblast growth factor receptor 171 and platelet-derived growth factor β receptor (PDGFβR).72

A host of substrates can be tyrosine phosphorylated byBcr-Abl (Table 1). Most important, because of autophosphorylation, there is a marked increase of phosphotyrosine on Bcr-Abl itself, which creates binding sites for the SH2 domains of other proteins. Generally, substrates of Bcr-Abl can be grouped according to their physiologic role into adapter molecules (such as Crkl and p62 DOK ), proteins associated with the organization of the cytoskeleton and the cell membrane (such as paxillin and talin), and proteins with catalytic function (such as the nonreceptor tyrosine kinase Fes or the phosphatase Syp). It is important to note that the choice of substrates depends on the cellular context. For example, Crkl is the major tyrosine-phosphorylated protein in CML neutrophils,73 whereas phosphorylated p62 DOK is predominantly found in early progenitor cells.74

Protein . Function . Reference .
P62 DOK Adapter 74
Crkl Adapter 73
Crk Adapter 13
Shc Adapter 75
Talin Cytoskeleton/cell membrane 76
Paxillin Cytoskeleton/cell membrane 77
Fak Cytoskeleton/cell membrane 78
Fes Myeloid differentiation 79
Ras-GAP Ras-GTPase 80
GAP-associated proteins Ras activation? 214
PLCγ Phospholipase 80
PI3 kinase (p85 subunit) Serine kinase 127
Syp Cytoplasmic phosphatase 83
Bap-1 14-3-3 protein 24
Cbl Unknown 81
Vav Hematopoietic differentiation 82
Protein . Function . Reference .
P62 DOK Adapter 74
Crkl Adapter 73
Crk Adapter 13
Shc Adapter 75
Talin Cytoskeleton/cell membrane 76
Paxillin Cytoskeleton/cell membrane 77
Fak Cytoskeleton/cell membrane 78
Fes Myeloid differentiation 79
Ras-GAP Ras-GTPase 80
GAP-associated proteins Ras activation? 214
PLCγ Phospholipase 80
PI3 kinase (p85 subunit) Serine kinase 127
Syp Cytoplasmic phosphatase 83
Bap-1 14-3-3 protein 24
Cbl Unknown 81
Vav Hematopoietic differentiation 82

Tyrosine phosphatases counterbalance and regulate the effects of tyrosine kinases under physiologic conditions, keeping cellular phosphotyrosine levels low. Two tyrosine phosphatases, Syp83 and PTP1B,84 have been shown to form complexes with Bcr-Abl, and both appear to dephosphorylate Bcr-Abl. Interestingly, PTP1B levels increase in a kinase-dependent manner, suggesting that the cell attempts to limit the impact of Bcr-Abl tyrosine kinase activity. At least in fibroblasts, transformation by Bcr-Abl is impaired by the overexpression of PTP1B.85Interestingly, we recently observed the up-regulation of receptor protein tyrosine phosphatase κ (RPTP-κ) with the inhibition of Bcr-Abl in BV173 cells treated with the tyrosine kinase inhibitor STI571,86 which suggests that the opposite effect may also occur. Thus, though the pivotal role of Bcr-Abl tyrosine kinase activity is clearly established, much remains to be learned about the significance of tyrosine phosphatases in the transformation process.

Activated signaling pathways and biologic properties of BCR-ABL–positive cells

Three major mechanisms have been implicated in the malignant transformation by Bcr-Abl, namely altered adhesion to stroma cells and extracellular matrix,87 constitutively active mitogenic signaling88 and reduced apoptosis89(Figure 5). A fourth possible mechanism is the recently described proteasome-mediated degradation of Abl inhibitory proteins.66

Mechanisms implicated in the pathogenesis of CML.

Mechanisms implicated in the pathogenesis of CML.

Altered adhesion properties

CML progenitor cells exhibit decreased adhesion to bone marrow stroma cells and extracellular matrix.87,90 In this scenario, adhesion to stroma negatively regulates cell proliferation, and CML cells escape this regulation by virtue of their perturbed adhesion properties. Interferon-α (IFN-α), an active therapeutic agent in CML, appears to reverse the adhesion defect.91Recent data suggest an important role for β-integrins in the interaction between stroma and progenitor cells. CML cells express an adhesion-inhibitory variant of β1 integrin that is not found in normal progenitors.92 On binding to their receptors, integrins are capable of initiating normal signal transduction from outside to inside93 it is thus conceivable that the transfer of signals that normally inhibit proliferation is impaired in CML cells. Because Abl has been implicated in the intracellular transduction of such signals, this process may be further disturbed by the presence of a large pool of Bcr-Abl protein in the cytoplasm. Furthermore, Crkl, one of the most prominent tyrosine-phosphorylated proteins in Bcr-Abl–transformed cells,73 is involved in the regulation of cellular motility94 and in integrin-mediated cell adhesion95 by association with other focal adhesion proteins such as paxillin, the focal adhesion kinase Fak, p130Cas,96 and Hef1.97 We recently demonstrated that Bcr-Abl tyrosine kinase up-regulates the expression of α6 integrin mRNA,86 which points to transcriptional activation as yet another possible mechanism by which Bcr-Abl may have an impact on integrin signaling. Thus, though there is sound evidence that Bcr-Abl influences integrin function, it is more difficult to determine the precise nature of the biologic consequences, and, at least in certain cellular systems, integrin function appears to be enhanced rather than reduced by Bcr-Abl.98

Activation of mitogenic signaling

Ras and the MAP kinase pathways.

Several links between Bcr-Abl and Ras have been defined. Autophosphorylation of tyrosine 177 provides a docking site for the adapter molecule Grb-2.57 Grb-2, after binding to the Sos protein, stabilizes Ras in its active GTP-bound form. Two other adapter molecules, Shc and Crkl, can also activate Ras. Both are substrates of Bcr-Abl73,99 and bind Bcr-Abl through their SH2 (Shc) or SH3 (Crkl) domains. The relevance of Ras activation by Crkl is, however, questionable because it appears to be restricted to fibroblasts.100 Moreover, direct binding of Crkl to Bcr-Abl is not required for the transformation of myeloid cells.101 Circumstantial evidence that Ras activation is important for the pathogenesis of Ph-positive leukemias comes from the observation that activating mutations are uncommon, even in the blastic phase of the disease,102 unlike in most other tumors. This implies that the Ras pathway is constitutively active, and no further activating mutations are required. There is still dispute as to which mitogen-activated protein (MAP) kinase pathway is downstream of Ras in Ph-positive cells. Stimulation of cytokine receptors such as IL-3 leads to the activation of Ras and the subsequent recruitment of the serine–threonine kinase Raf to the cell membrane.103 Raf initiates a signaling cascade through the serine–threonine kinases Mek1/Mek2 and Erk, which ultimately leads to the activation of gene transcription.104 Although some data indicate that this pathway may be activated only in v-abl– but not in BCR-ABL–transformed cells,105 this view has recently been challenged.106 Moreover, activation of the Jnk/Sapk pathway by Bcr-Abl has been demonstrated and is required for malignant transformation107 thus, signaling from Ras may be relayed through the GTP–GDP exchange factor Rac108 to Gckr (germinal center kinase related)109 and further down to Jnk/Sapk (Figure 6). There is also some evidence that p38, the third pillar of the MAP kinase pathway, is also activated in BCR-ABL–transformed cells, and there are other pathways with mitogenic potential. In any case, the signal is eventually transduced to the transcriptional machinery of the cell.

Signaling pathways with mitogenic potential in

BCR-ABL–transformed cells. The activation of individual paths depends on the cell type, but the MAP kinase system appears to play a central role. Activation of p38 has been demonstrated only in v-abl–transformed cells, whereas data forBCR-ABL–expressing cells are missing.

Signaling pathways with mitogenic potential in

BCR-ABL–transformed cells. The activation of individual paths depends on the cell type, but the MAP kinase system appears to play a central role. Activation of p38 has been demonstrated only in v-abl–transformed cells, whereas data forBCR-ABL–expressing cells are missing.

It is also possible that Bcr-Abl uses growth factor pathways in a more direct way. For example, association with the βc subunit of the IL-3 receptor110 and the Kit receptor111 has been observed. Interestingly, the pattern of tyrosine-phosphorylated proteins seen in normal progenitor cells after stimulation with Kit ligand is similar to the pattern seen in CML progenitor cells.112 Dok-1 (p62 DOK ), one of the most prominent phosphoproteins in this setting, forms complexes with Crkl, RasGAP, and Bcr-Abl. In fact, there may be a whole family of related proteins with similar functions—for example, the recently described Dok-2 (p56 DOK 2).113 Somewhat surprisingly, p62 DOK is essential for transformation of Rat-1 fibroblasts but not for growth-factor independence of myeloid cells114 thus, its true role remains to be defined.

Jak-Stat pathway.

The first evidence for involvement of the Jak-Stat pathway came from studies in v-abl–transformed B cells.62 Constitutive phosphorylation of Stat transcription factors (Stat1 and Stat5) has since been reported in several BCR-ABL–positive cell lines115 and in primary CML cells,116 and Stat5 activation appears to contribute to malignant transformation.117 Although Stat5 has pleiotropic physiologic functions,118 its effect in BCR-ABL–transformed cells appears to be primarily anti-apoptotic and involves transcriptional activation of Bcl-xL.119,120In contrast to the activation of the Jak-Stat pathway by physiologic stimuli, Bcr-Abl may directly activate Stat1 and Stat5 without prior phosphorylation of Jak proteins. There seems to be specificity for Stat6 activation by P190 BCR-ABL proteins as opposed to P210 BCR-ABL .115 It is tempting to speculate that the predominantly lymphoblastic phenotype in these leukemias is related to this peculiarity.

The role of the Ras and Jak-Stat pathways in the cellular response to growth factors could explain the observation that BCR-ABLrenders a number of growth factor–dependent cell lines factor independent.105,121 In some experimental systems there is evidence for an autocrine loop dependent on the Bcr-Abl–induced secretion of growth factors,122 and it was recently reported that Bcr-Abl induces an IL-3 and G-CSF autocrine loop in early progenitor cells.123 Interestingly, Bcr-Abl tyrosine kinase activity may induce expression not only of cytokines but also of growth factor receptors such as the oncostatin M β receptor.86 One should bear in mind, however, that during the chronic phase, CML progenitor cells are still dependent on external growth factors for their survival and proliferation,124though less than normal progenitors.125 A recent study sheds fresh light on this issue. FDCPmix cells transduced with a temperature-sensitive mutant of BCR-ABL have a reduced requirement for growth factors at the kinase permissive temperature without differentiation block.126 This situation resembles chronic-phase CML, in which the malignant clone has a subtle growth advantage while retaining almost normal differentiation capacity.

PI3 kinase pathway.

PI3 kinase activity is required for the proliferation ofBCR-ABL–positive cells.127 Bcr-Abl forms multimeric complexes with PI3 kinase, Cbl, and the adapter molecules Crk and Crkl,95 in which PI3 kinase is activated. The next relevant substrate in this cascade appears to be the serine–threonine kinase Akt.128 This kinase had previously been implicated in anti-apoptotic signaling.129 A recent report placed Akt in the downstream cascade of the IL-3 receptor and identified the pro-apoptotic protein Bad as a key substrate of Akt.130Phosphorylated Bad is inactive because it is no longer able to bind anti-apoptotic proteins such as BclXL and it is trapped by cytoplasmic 14-3-3 proteins. Altogether this indicates that Bcr-Abl might be able to mimic the physiologic IL-3 survival signal in a PI3 kinase-dependent manner (see also below). Ship131 and Ship-2,132 2 inositol phosphatases with somewhat different specificities, are activated in response to growth factor signals and by Bcr-Abl. Thus, Bcr-Abl appears to have a profound effect on phosphoinositol metabolism, which might again shift the balance to a pattern similar to physiologic growth factor stimulation.

Myc pathway.

Overexpression of Myc has been demonstrated in many human malignancies. It is thought to act as a transcription factor, though its target genes are largely unknown. Activation of Myc by Bcr-Abl is dependent on the SH2 domain, and the overexpression of Myc partially rescues transformation-defective SH2 deletion mutants whereas the overexpression of a dominant-negative mutant suppresses transformation.133 The pathway linking Myc to the SH2 domain of Bcr-Abl is still unknown. However, results obtained in v-abl–transformed cells suggest that the signal is transduced through Ras/Raf, cyclin-dependent kinases (cdks), and E2F transcription factors that ultimately activate the MYC promoter.134 Similar results were reported for BCR-ABL–transformed murine myeloid cells.135 How these findings relate to human Ph-positive cells is unknown. It seems likely that the effects of Myc in Ph-positive cells are probably not different from those in other tumors. Depending on the cellular context, Myc may constitute a proliferative or an apoptotic signal.136,137 It is therefore likely that the apoptotic arm of its dual function is counterbalanced in CML cells by other mechanisms, such as the PI3 kinase pathway.

Inhibition of apoptosis

Expression of Bcr-Abl in factor-dependent murine138and human122 cell lines prevents apoptosis after growth-factor withdrawal, an effect that is critically dependent on tyrosine kinase activity and that correlates with the activation of Ras.88,139 Moreover, several studies showed thatBCR-ABL–positive cell lines are resistant to apoptosis induced by DNA damage.89,140 The underlying biologic mechanisms are still not well understood. Bcr-Abl may block the release of cytochrome C from the mitochondria and thus the activation of caspases.141,142 This effect upstream of caspase activation might be mediated by the Bcl-2 family of proteins. Bcr-Abl has been shown to up-regulate Bcl-2 in a Ras-143 or a PI3 kinase-dependent128 manner in Baf/3 and 32D cells, respectively. Moreover, as mentioned previously, BclxL is transcriptionally activated by Stat5 in BCR-ABL–positive cells.119,120

Another link between BCR-ABL and the inhibition of apoptosis might be the phosphorylation of the pro-apoptotic protein Bad. In addition to Akt, Raf-1, immediately downstream of Ras, phosphorylates Bad on 2 serine residues.144,145 Two recent studies provided evidence that the survival signal provided by Bcr-Abl is at least partially mediated by Bad and requires targeting of Raf-1 to the mitochondria.146,147 It is also possible that Bcr-Abl inhibits apoptosis by down-regulating interferon consensus sequence binding protein (ICSBP).148,149 These data are interesting because ICSBP knockout mice develop a myeloproliferative syndrome,150 and hematopoietic progenitor cells from ICSBP−/− mice show altered responses to cytokines.151 The connection to interferon α, an active agent in the treatment of CML, is obvious.

It becomes clear that the multiple signals initiated by Bcr-Abl have proliferative and anti-apoptotic qualities that are frequently difficult to separate. Thus, Bcr-Abl may shift the balance toward the inhibition of apoptosis while simultaneously providing a proliferative stimulus. This is in line with the concept that a proliferative signal leads to apoptosis unless it is counterbalanced by an anti-apoptotic signal,152 and Bcr-Abl fulfills both requirements at the same time. There is, however, controversy. One report found 32D cells transfected with BCR-ABL to be more sensitive to IR than the parental cells,153 whereas 2 other studies failed to detect any difference between CML and normal primary progenitor cells with regard to their sensitivity to IR and growth factor withdrawal.124,154 Furthermore, based on results obtained in transfected cell systems, it was suggested that Bcr-Abl inhibits apoptosis mediated by the Fas receptor/Fas ligand system.155 However, though there may be a role for this system in mediating the clinical response to interferon-α,156 there is no indication that Fas-triggered apoptosis is defective in primary CML cells or in “natural” Ph-positive cell lines.157 Moreover, Bcr-Abl accelerates C2 ceramide-induced apoptosis,158 and it does not protect against natural killer cell-induced apoptosis.159 These inconsistencies may reflect genuine differences between cell lines and primary cells. On the other hand, it is debatable whether complete growth-factor withdrawal and IR constitute stimuli that have much physiologic relevance. To allow for a representative comparison, it would be crucial to define the signals that induce apoptosis in vivo.

Degradation of inhibitory proteins.

The recent discovery that Bcr-Abl induces the proteasome-mediated degradation of Abi-1 and Abi-2,66 2 proteins with inhibitory function, may be the first indication of yet another way by which Bcr-Abl induces cellular transformation. Most compelling, the degradation of Abi-1 and Abi-2 is specific for Ph-positive acute leukemias and is not seen in Ph-negative samples of comparable phenotype. The overall significance of this observation remains to be seen, and one must bear in mind that the data refer to acute leukemias and not to chronic phase CML. It is nevertheless tempting to speculate that other proteins, whose level of expression is regulated through the proteasome pathway, may also be degraded. A good candidate would be the cell cycle inhibitor p27, but to our knowledge no data are available yet.


Contents

There has been a long tradition of creating molecular models from physical materials. Perhaps the best known is Crick and Watson's model of DNA built from rods and planar sheets, but the most widely used approach is to represent all atoms and bonds explicitly using the "ball and stick" approach. This can demonstrate a wide range of properties, such as shape, relative size, and flexibility. Many chemistry courses expect that students will have access to ball and stick models. One goal of mainstream molecular graphics has been to represent the "ball and stick" model as realistically as possible and to couple this with calculations of molecular properties.

Figure 1 shows a small molecule ( NH
3 CH
2 CH
2 C(OH)(PO
3 H)(PO
3 H)- ), as drawn by the Jmol program. It is important to realize that the colors and shapes are purely a convention, as individual atoms are not colored, nor do they have hard surfaces. Bonds between atoms are also not rod-shaped.

Comparison of physical models with molecular graphics Edit

Physical models and computer models have partially complementary strengths and weaknesses. Physical models can be used by those without access to a computer and now can be made cheaply out of plastic materials. Their tactile and visual aspects cannot be easily reproduced by computers (although haptic devices have occasionally been built). On a computer screen, the flexibility of molecules is also difficult to appreciate illustrating the pseudorotation of cyclohexane is a good example of the value of mechanical models.

However, it is difficult to build large physical molecules, and all-atom physical models of even simple proteins could take weeks or months to build. Moreover, physical models are not robust and they decay over time. Molecular graphics is particularly valuable for representing global and local properties of molecules, such as electrostatic potential. Graphics can also be animated to represent molecular processes and chemical reactions, a feat that is not easy to reproduce physically.

Initially the rendering was on early Cathode ray tube screens or through plotters drawing on paper. Molecular structures have always been an attractive choice for developing new computer graphics tools, since the input data are easy to create and the results are usually highly appealing. The first example of MG was a display of a protein molecule (Project MAC, 1966) by Cyrus Levinthal and Robert Langridge. Among the milestones in high-performance MG was the work of Nelson Max in "realistic" rendering of macromolecules using reflecting spheres.

By about 1980 many laboratories both in academia and industry had recognized the power of the computer to analyse and predict the properties of molecules, especially in materials science and the pharmaceutical industry. The discipline was often called "molecular graphics" and in 1982 a group of academics and industrialists in the UK set up the Molecular Graphics Society (MGS). Initially much of the technology concentrated either on high-performance 3D graphics, including interactive rotation or 3D rendering of atoms as spheres (sometimes with radiosity). During the 1980s a number of programs for calculating molecular properties (such as molecular dynamics and quantum mechanics) became available and the term "molecular graphics" often included these. As a result, the MGS has now changed its name to the Molecular Graphics and Modelling Society (MGMS).

The requirements of macromolecular crystallography also drove MG 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.

In 2009 BALLView became the first software to use realtime Raytracing for molecular graphics.

Both computer technology and graphic arts have contributed to molecular graphics. The development of structural biology in the 1950s led to a requirement to display molecules with thousands of atoms. The existing computer technology was limited in power, and in any case a naive depiction of all atoms left viewers overwhelmed. Most systems therefore used conventions where information was implicit or stylistic. Two vectors meeting at a point implied an atom or (in macromolecules) a complete residue (10-20 atoms).

The macromolecular approach was popularized by Dickerson and Geis' presentation of proteins and the graphic work of Jane Richardson through high-quality hand-drawn diagrams such as the "ribbon" representation. In this they strove to capture the intrinsic 'meaning' of the molecule. This search for the "messages in the molecule" has always accompanied the increasing power of computer graphics processing. Typically the depiction would concentrate on specific areas of the molecule (such as the active site) and this might have different colors or more detail in the number of explicit atoms or the type of depiction (e.g., spheres for atoms).

In some cases the limitations of technology have led to serendipitous methods for rendering. Most early graphics devices used vector graphics, which meant that rendering spheres and surfaces was impossible. Michael Connolly's program "MS" calculated points on the surface-accessible surface of a molecule, and the points were rendered as dots with good visibility using the new vector graphics technology, such as the Evans and Sutherland PS300 series. Thin sections ("slabs") through the structural display showed very clearly the complementarity of the surfaces for molecules binding to active sites, and the "Connolly surface" became a universal metaphor.

The relationship between the art and science of molecular graphics is shown in the exhibitions sponsored by the Molecular Graphics Society. [ citation needed ] Some exhibits are created with molecular graphics programs alone, while others are collages, or involve physical materials. An example from Mike Hann (1994), inspired by Magritte's painting Ceci n'est pas une pipe, uses an image of a salmeterol molecule. "Ceci n'est pas une molecule," writes Mike Hann, "serves to remind us that all of the graphics images presented here are not molecules, not even pictures of molecules, but pictures of icons which we believe represent some aspects of the molecule's properties." [ citation needed ]

Colour molecular graphics is often use on chemistry journal covers in an artistic manner. [3]

Space-filling models Edit

Fig. 4 is a "space-filling" representation of formic acid, where atoms are drawn as solid spheres to suggest the space they occupy. This and all space-filling models are necessarily icons or abstractions: atoms are nuclei with electron "clouds" of varying density surrounding them, and as such have no actual surfaces. For many years the size of atoms has been approximated by physical models (CPK) in which the volumes of plastic balls describe where much of the electron density is to be found (often sized to van der Waals radii). That is, the surface of these models is meant to represent a specific level of density of the electron cloud, not any putative physical surface of the atom.

Since the atomic radii (e.g. in Fig. 4) are only slightly less than the distance between bonded atoms, the iconic spheres intersect, and in the CPK models, this was achieved by planar truncations along the bonding directions, the section being circular. When raster graphics became affordable, one of the common approaches was to replicate CPK models in silico. It is relatively straightforward to calculate the circles of intersection, but more complex to represent a model with hidden surface removal. A useful side product is that a conventional value for the molecular volume can be calculated.

The use of spheres is often for convenience, being limited both by graphics libraries and the additional effort required to compute complete electronic density or other space-filling quantities. It is now relatively common to see images of surfaces that have been colored to show quantities such as electrostatic potential. Common surfaces in molecular visualization include solvent-accessible ("Lee-Richards") surfaces, solvent-excluded ("Connolly") surfaces, and isosurfaces. The isosurface in Fig. 5 appears to show the electrostatic potential, with blue colors being negative and red/yellow (near the metal) positive (there is no absolute convention of coloring, and red/positive, blue/negative are often reversed). Opaque isosurfaces do not allow the atoms to be seen and identified and it is not easy to deduce them. Because of this, isosurfaces are often drawn with a degree of transparency.

Early interactive molecular computer graphics systems were vector graphics machines, which used stroke-writing vector monitors, sometimes even oscilloscopes. The electron beam does not sweep left-and-right as in a raster display. The display hardware followed a sequential list of digital drawing instructions (the display list), directly drawing at an angle one stroke for each molecular bond. When the list was complete, drawing would begin again from the top of the list, so if the list was long (a large number of molecular bonds), the display would flicker heavily. Later vector displays could rotate complex structures with smooth motion, since the orientation of all of the coordinates in the display list could be changed by loading just a few numbers into rotation registers in the display unit, and the display unit would multiply all coordinates in the display list by the contents of these registers as the picture was drawn.

The early black-and white vector displays could somewhat distinguish for example a molecular structure from its surrounding electron density map for crystallographic structure solution work by drawing the molecule brighter than the map. Color display makes them easier to tell apart. During the 1970s two-color stroke-writing Penetron tubes were available, but not used in molecular computer graphics systems. In about 1980 Evans & Sutherland made the first practical full-color vector displays for molecular graphics, typically attached to an E&S PS-2 or MPS (MPS or Multi-Picture-System refers to several displays using a common graphics processor rack) graphics processor. This early color display (the CSM or Color-Shadow-Mask) was expensive (around $50,000), because it was originally engineered to withstand the shaking of a flight-simulator motion base and because the vector scan was driven by a pair (X,Y) of 1Kw amplifiers. These systems required frequent maintenance and the wise user signed a flat rate Service Contract with E&S. The newer E&S PS-300 series graphics processors used less expensive color displays with raster scan technology and the entire system could be purchased for less than the older CSM display alone. [4]

Color raster graphics display of molecular models began around 1978 as seen in this paper by Porter [5] on spherical shading of atomic models. Early raster molecular graphics systems displayed static images that could take around a minute to generate. Dynamically rotating color raster molecular display phased in during 1982–1985 with the introduction of the Ikonas programmable raster display.

Molecular graphics has always pushed the limits of display technology, and has seen a number of cycles of integration and separation of compute-host and display. Early systems like Project MAC were bespoke and unique, but in the 1970s the MMS-X and similar systems used (relatively) low-cost terminals, such as the Tektronix 4014 series, often over dial-up lines to multi-user hosts. The devices could only display static pictures but were able to evangelize MG. In the late 1970s, it was possible for departments (such as crystallography) to afford their own hosts (e.g., PDP-11) and to attach a display (such as Evans & Sutherland's PS-1) directly to the bus. The display list was kept on the host, and interactivity was good since updates were rapidly reflected in the display—at the cost of reducing most machines to a single-user system.

In the early 1980s, Evans & Sutherland (E&S) decoupled their PS300 graphics processor/display, which contained its own display information transformable through a dataflow architecture. Complex graphical objects could be downloaded over a serial line (e.g. 9600, 56K baud) or Ethernet interface and then manipulated without impact on the host. The architecture was excellent for high performance display but very inconvenient for domain-specific calculations, such as electron-density fitting and energy calculations. Many crystallographers and modellers spent arduous months trying to fit such activities into this architecture. E&S designed a card for the PS-300 which had several calculation algorithms using a 100 bit wide finite state machine in an attempt to simplify this process but it was so difficult to program that it quickly became obsolete. [6]

The benefits for MG were considerable, but by the later 1980s, UNIX workstations such as Sun-3 with raster graphics (initially at a resolution of 256 by 256) had started to appear. Computer-assisted drug design in particular required raster graphics for the display of computed properties such as atomic charge and electrostatic potential. Although E&S had a high-end range of raster graphics (primarily aimed at the aerospace industry) they failed to respond to the low-end market challenge where single users, rather than engineering departments, bought workstations. As a result, the market for MG displays passed to Silicon Graphics, coupled with the development of minisupercomputers (e.g., CONVEX and Alliant) which were affordable for well-supported MG laboratories. Silicon Graphics provided a graphics language, IrisGL, which was easier to use and more productive than the PS300 architecture. Commercial companies (e.g., Biosym, Polygen/MSI) ported their code to Silicon Graphics, and by the early 1990s, this was the "industry standard". Dial boxes were often used as control devices.

Stereoscopic displays were developed based on liquid crystal polarized spectacles, and while this had been very expensive on the PS2, it now became a commodity item. A common alternative was to add a polarizable screen to the front of the display and to provide viewers with extremely cheap spectacles with orthogonal polarization for separate eyes. With projectors such as Barco, it was possible to project stereoscopic display onto special silvered screens and supply an audience of hundreds with spectacles. In this way molecular graphics became universally known within large sectors of chemical and biochemical science, especially in the pharmaceutical industry. Because the backgrounds of many displays were black by default, it was common for modelling sessions and lectures to be held with almost all lighting turned off.

In the last decade almost all of this technology has become commoditized. IrisGL evolved to OpenGL so that molecular graphics can be run on any machine. In 1992, Roger Sayle released his RasMol program into the public domain. RasMol contained a very high-performance molecular renderer that ran on Unix/X Window, and Sayle later ported this to the Windows and Macintosh platforms. The Richardsons developed kinemages and the Mage software, which was also multi-platform. By specifying the chemical MIME type, molecular models could be served over the Internet, so that for the first time MG could be distributed at zero cost regardless of platform. In 1995, Birkbeck College's crystallography department used this to run "Principles of Protein Structure", the first multimedia course on the Internet, which reached 100 to 200 scientists.

MG continues to see innovation that balances technology and art, and currently zero-cost or open source programs such as PyMOL and Jmol have very wide use and acceptance.

Recently the widespread diffusion of advanced graphics hardware has improved the rendering capabilities of the visualization tools. The capabilities of current shading languages allow the inclusion of advanced graphic effects (like ambient occlusion, cast shadows and non-photorealistic rendering techniques) in the interactive visualization of molecules. These graphic effects, beside being eye candy, can improve the comprehension of the three-dimensional shapes of the molecules. An example of the effects that can be achieved exploiting recent graphics hardware can be seen in the simple open source visualization system QuteMol.

Reference frames Edit

Drawing molecules requires a transformation between molecular coordinates (usually, but not always, in Angstrom units) and the screen. Because many molecules are chiral it is essential that the handedness of the system (almost always right-handed) is preserved. In molecular graphics the origin (0, 0) is usually at the lower left, while in many computer systems the origin is at top left. If the z-coordinate is out of the screen (towards the viewer) the molecule will be referred to right-handed axes, while the screen display will be left-handed.

Molecular transformations normally require:

  • scaling of the display (but not the molecule).
  • translations of the molecule and objects on the screen.
  • rotations about points and lines.

Conformational changes (e.g. rotations about bonds) require rotation of one part of the molecule relative to another. The programmer must decide whether a transformation on the screen reflects a change of view or a change in the molecule or its reference frame.

Simple Edit

In early displays only vectors could be drawn e.g. (Fig. 7) which are easy to draw because no rendering or hidden surface removal is required.

On vector machines the lines would be smooth but on raster devices Bresenham's algorithm is used (note the "jaggies" on some of the bonds, which can be largely removed with antialiasing software.)

Atoms can be drawn as circles, but these should be sorted so that those with the largest z-coordinates (nearest the screen) are drawn last. Although imperfect, this often gives a reasonably attractive display. Other simple tricks which do not include hidden surface algorithms are:

  • coloring each end of a bond with the same color as the atom to which it is attached (Fig. 7).
  • drawing less than the whole length of the bond (e.g. 10–90%) to simulate the bond sticking out of a circle.
  • adding a small offset white circle within the circle for an atom to simulate reflection.

Typical pseudocode for creating Fig. 7 (to fit the molecule exactly to the screen):

Note that this assumes the origin is in the bottom left corner of the screen, with Y up the screen. Many graphics systems have the origin at the top left, with Y down the screen. In this case the lines (1) and (2) should have the y coordinate generation as:

Changes of this sort change the handedness of the axes so it is easy to reverse the chirality of the displayed molecule unless care is taken.

Advanced Edit

For greater realism and better comprehension of the 3D structure of a molecule many computer graphics algorithms can be used. For many years molecular graphics has stressed the capabilities of graphics hardware and has required hardware-specific approaches. With the increasing power of machines on the desktop, portability is more important and programs such as Jmol have advanced algorithms that do not rely on hardware. On the other hand, recent graphics hardware is able to interactively render very complex molecule shapes with a quality that would not be possible with standard software techniques.

Developer(s) Approximate date Technology Comments
Crystallographers < 1960 Hand-drawn Crystal structures, with hidden atom and bond removal. Often clinographic projections.
Johnson, Motherwell ca 1970 Pen plotter ORTEP, PLUTO. Very widely deployed for publishing crystal structures.
Cyrus Levinthal, Bob Langridge, Ward, Stots [7] 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 [8] 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 [9] 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 [10] 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 [11] 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 [12] 1971 Adage AGT/50 display Interactive molecular structure viewing system. Mathematics of nested rotation and for laboratory-space rotation.
Perkins, Piper, Tattam, White [13] 1971 Honeywell DDP 516 computer, EAL TR48 analog computer, Lanelec oscilloscope, 7 linear potentiometers. Stereo. Interactive molecular structure viewing system.
Wright [14] [15] [16] 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 [17] 1972 Oxford Univ.: 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 Leeds Univ.: 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: [18] [19] Washington Univ. at 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 [20] 1974 DEC PDP-10 computer, Adage display, push buttons, keyboard, knobs Prototype large-molecule crystallographic structure solution system.
Stellman [21] 1975 Princeton: 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, [22] 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.) Univ, of Calif. 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. [23]
Rosenberger et al. 1976 MMS-X: [24] Washington Univ. at 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 [16] [25] [26] [27] [28] 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. [29]
Jones 1978 FRODO and RING [30] [31] 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 [32] 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- ICM-Browser proprietary free download for Windows, Mac, and Linux. [33] [34]
1998- MarvinSketch & MarvinView. MarvinSpace (2005) proprietary Java applet or stand-alone application.
Community efforts 2000- DINO, Jmol, PyMol, Avogadro, PDB, OpenStructure Open-source Java applet or stand-alone application.
NOCH 2002- NOC Open source code molecular structure explorer
LION Bioscience / EMBL 2004- SRS 3D Free, open-source system based on Java3D. Integrates 3D structures with sequence and feature data (domains, SNPs, etc.).
San Diego Supercomputer Center 2006- Sirius Free for academic/non-profit institutions
Community efforts 2009- HTML5/JavaScript viewers (ChemDoodle Web Components, GLMol, jolecule, pv, Molmil, iCn3D, 3DMol, NGL, Speck, xtal.js, UglyMol, LiteMol, JSmol) All Open-source. Require WebGL support in the browser (except for JSmol).

Electronic Richards Box Systems Edit

Before computer graphics could be employed, around 1976-1977 (references and explanation a few paragraphs below), mechanical methods were used to fit large molecules to their electron density maps. Using techniques of X-ray crystallography crystal of a substance were bombarded with X-rays, and the diffracted beams that came off were assembled by computer using a Fourier transform into a usually blurry 3-D image of the molecule, made visible by drawing contour circles around high electron density to produce a contoured electron density map. [ citation needed ]

In the earliest days, contoured electron density maps were hand drawn on large plastic sheets. Sometimes, bingo chips were placed on the plastic sheets where atoms were interpreted to be.

This was superseded by the Richards Box [35] in which an adjustable brass Kendrew molecular model was placed front of a 2-way mirror, behind which were plastic sheets of the electron density map. This optically superimposed the molecular model and the electron density map. The model was moved to within the contour lines of the superimposed map. Then, atomic coordinates were recorded using a plumb bob and a meter stick. Computer graphics held out the hope of vastly speeding up this process, as well as giving a clearer view, because the small region of interest could be viewed without obscuring clutter from the rest of the contoured molecule, could be contoured by orthogonal rings of electron density instead of rings in just one plane giving more of a uniform cloud view, and the region of interest could under joystick control be inspected from any direction, not just the viewing direction through the glass pane of the Richard's Box.

A noteworthy attempt to overcome the low speed of graphics displays of the early 1970s took place at Washington University in St. Louis, USA. [18] [19] Dave Barry's group attempted to leapfrog the state of the art in graphics displays by making custom display hardware to display images complex enough for large-molecule crystallographic structure solution, fitting molecules to their electron-density maps. The MMS-4 (table above) display modules were slow and expensive, so a second generation of modules was produced for the MMS-X [24] (table above) system.

The first large molecule whose atomic structure was partly determined on a molecular computer graphics system was Transfer RNA by Sung-Hou Kim's team in 1976. [36] [37] after initial fitting on a mechanical Richards Box. The first large molecule whose atomic structure was entirely determined on a molecular computer graphics system is said to be neurotoxin A from venom of the Philippines sea snake, by Tsernoglou, Petsko, and Tu, [38] with a statement of being first [29] in 1977. The Richardson group published partial atomic structure results [39] of the protein superoxide dismutase the same year, in 1977. All of these were done using the GRIP-75 system (table above).

Other structure fitting systems, FRODO, RING, Builder, MMS-X, etc. (table above) succeeded in solving large protein structres too in the years 1977-1980.

The reason that most of these systems succeeded in just those years, 1976-1980 not earlier or later, and within a short timespan had to do with the arrival of commercial hardware that was powerful enough. [ citation needed ] Two things were needed and arrived at about the same time. First, electron density maps are large and require either a computer with at least a 24-bit address space or a combination of a computer with a lesser 16-bit address space plus several years to overcome the difficulties of an address space that is smaller than the data. The second arrival was that of interactive computer graphics displays that were fast enough to display electron-density maps, whose contour circles require the display of numerous short vectors. The first such displays were the Vector General Series 3 and the Evans and Sutherland Picture System 2, MultiPicture System, and PS-300. [ citation needed ]

Later, [ when? ] fitting of the molecular structure to the electron density map was largely automated by algorithms with computer graphics a guide to the process. Examples are the XtalView and XFit programs. [ citation needed ]


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Acknowledgements

This work was supported by the National Science Foundation under contract ACI 9624034 (CAREER Award), through the LSSDSV program under contract ACI 9982251, and a large ITR grant. We gratefully acknowledge the support of the W.M. Keck Foundation provided to the UC Davis Center for Active Visualization in the Earth Sciences (KeckCAVES). We thank Nina Amenta, Oliver Kreylos, and Benjamin Ahlborn for their contribution to the design and implementation of the methods and tools described in this paper. We thank John S. Werner, Robert Zawadzki, Joe Izaatt, Stacey Choi, and Alfred Fuller for their contributions to the retinal imaging project. We thank Yusu Wang, Peer-Timo Bremer, and Valerio Pascucci for their contributions to the protein visualization project. We further thank the members of the Visualization and Computer Graphics Research Group at IDAV at the University of California, Davis, and the members of the BDTNP at Lawrence Berkeley National Laboratory. The monkey brain data set is courtesy of Edward G Jones, UC Davis Center for Neuroscience.

This article has been published as part of BMC Cell Biology Volume 8 Supplement 1, 2007: 2006 International Workshop on Multiscale Biological Imaging, Data Mining and Informatics. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2121/8?issue=S1


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Features of Achieve include:

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