Mia Huddleston Week 8

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Preparation for Week 9 Journal Club

10 Biological Terms from Article

  1. Glycoprotein: one of a group of compounds consisting of a protein combined with a carbohydrate (such as galactose or mannose). Examples of glycoproteins are certain enzymes, hormones, and antigens.
  2. Glycosylation: The process in which a carbohydrate is joined to another molecule, such as a protein to form a glycoprotein or to a lipid to form a glycolipid. Glycosylation occurs in the rough endoplasmic reticulum and the Golgi apparatus of cells
  3. Virions: A completed virus particle consisting of a nucleic acid core and a protein coat.
  4. Root mean square deviation: The positive square root of the mean squared deviation
  5. Immunochemical: any specific immunological reagent that consists of or incorporates an antigen or an antibody, especially one of commerce.
  6. Annealing: A form of heat treatment applied to a metal to soften it, relieve internal stresses and instabilities, and make it easier to work or machine. It consists of heating the metal to a specified temperature for a specified time, both of which depend on the metal involved, and then allowing it to cool slowly. It is applied to both ferrous and nonferrous metals and a similar process can be applied to other materials, such as glass.
  7. Beta-turns: a short stretch of polypeptide chain that allows the main direction of the chain to change
  8. Dihedrals: An angle formed by the intersection of two planes (e.g. two faces of a polyhedron). The dihedral angle is the angle formed by taking a point on the line of intersection and drawing two lines from this point, one in each plane, perpendicular to the line of intersection.
  9. Fab fragment: One of the fragments produced by partial digestion of immunoglobulin with the proteolytic enzyme papain. It corresponds to an arm of the Y-shaped molecule and consists of an entire light chain paired with part of a heavy chain, complete with the antigen-binding site. Digestion of an IgG immunoglobulin molecule will thus yield two identical Fab fragments, representing the separated arms of the Y, and an Fc fragment, which corresponds to the stem of the Y and consists of the remaining regions of the heavy chains paired via the disulphide bond of the hinge region. Compare F(ab′)2 fragment.
  10. Motif: A recurring theme, idea, or element in a work of art or an artist's oeuvre. In French art, artists who painted in the open air were sometimes described as painting ‘sur le motif

Outline of Article

Introduction

  • the HIV virus enters the host cell and binds to the CD4 T cell revealing the binding site; V3 loop
  • V3 keeps HIV-1 from escaping entry inhibitors
  • Although the V3 loop is highly variable, there are also highly conserved areas that suggest it connects with the conserved regions of HIV-1 strains
    • this is important in finding an anit-AIDS drug that can match these conserved regions
  • variability between V3 loop sequences may not be due to geographic locations of the individuals
    • this causes problems
    • solving this problem is made more difficult by the limits on V3 models
  • most research of V3 is being done on HIV-1 subtype B in North and South America, Western Europe, Japan, Australia, and Thailand
  • while subtype A is being studied in Central Africa, Thailand, and Eastern Europe
    • Greatest interest in this because it has not been put into practice
  • 3D structures of the HIV-1 subtype A V3 loop is looked at

Methods

  • 3D models were compared between NMR spectroscopy and X-ray studies
  • Secondary V3 structures were identified using beta turns and inter-atomic distances
  • their 3D V3 structures were compared by their root-mean-square deviations in atomic coordinates, and in terms of the dihedrals
    • RMSD values were calculated for the entire structure and its individual fragments
  • Molecular dynamics computations were found of the structures
    • every 10 ps data of the geometric parameters and their energy characteristics were recorded and the MD conformations were compared
  • Molecular docking of the V3 loop with two different peptides were simulated using the Hex 4.5 program

Results and Discussions

  • four models with the most preferable structures of the HIV-1 subtype A V3 loop were determined using these methods
    • the cRMSD values were between 5.6 and 8.6 Å meaning that they vary in the geometric space of Cartesian coordinates
    • the space of dihedral angles also shows varying
    • however there are three areas that show close structural similarity
      • these similarities are important to AIDS pathogenesis
  • Structurally rigid street 5-7 embraces one of the sites used by the virus for defense against neutralizing antibodies and elevation of its infectivity
  • inflexible pentapeptide 15-19 shows the majority of the contacts with antibodies and determines their binding
  • cRMSD values are compared between different segments
  • structural conservatism happens in the space of atomic coordinates but not in the space of dihedral angles
    • but, comparative analysis of the structure points to the conservation of individual V3 residues
    • all give rise to similar folds in V3 segments 3-7, 15-19, and 28-32
  • the spatial folds of the V3 segments make the signal structure necessary to be recognized by target cells
  • the low energy structure will be used as the conformation relevant
  • Figure 2 shows the most likely 3D structure of the V3 loop
  • Figure 3 shows the secondary structures of the V3 conformation
    • also shoes the availability of its structural elements
    • similar structures were seen between the V3 portion in the HIV-Haiti and MN isolates as in crystal for the V3 peptides bound to the Fabs of monoclonal antibodies
      • especially in 59.1
    • Figure 3 helps to indicate that C-terminal V3 region longs for the helix-like structures
  • Beta turns recurring in the central portion of V3 loop and in their N- and C- terminals may be used as the framework helping the virus during replication
  • Figure 4 indicates the time dependence of the cRMSD values between all of the MD confirmations and the input structure of the SA-V3 loop
  • Figure 5 shows the results of the study on the conformational V3 freedom carried
    • shows that with the immunogenic crest of the SA-V3 loop, its longer central sites actually preserve their 3D folds within computational time
  • Figure 6 shoes the behavior of the SA-V3 loop in the geometric space of dihedral angles
  • FKBP and CycA peptides may serve as chemicals for anti-AIDS drug studies
  • Figure 7a shows the structural complexes of the SA-V3 loop with CycA
    • shows the region of V3 that becomes close with the ligand and also has specific high-affinity interactions
  • Figure 7b shows the structural complex of FKBP peptides

Conclusion

  • A new way of reconstructing the V3 structure was developed
  • they were able to define the low energy conformations of the V3 loop and find its most probable 3D structure
  • they found that some fragments were found to retain the spatial folds
  • the V3 site may be involved in eliciting neutralizing antibody responses, affecting HIV-1 tropism, and increasing the immunogenicity of AIDS drugs
    • but, not all of the amino acids in these sections have been fully studied
  • More studies on analogous structures must be carried out for the other subtypes


  • What is the main result (message) presented in this paper?
    • A probable 3D construction of the HIV-1 subtype A V3 look was created and can be used to help construct an anti-AIDS drug
  • What is the importance or significance of this work?
    • This work helps to find drugs to prevent AIDS using the structure of the conserved region on the V3 loop of HIV-1 subtype A
  • What were the limitations in previous studies that led them to perform this work?
    • Previously there were not as many ways of determining the structure of this region as they were able to do in this work
  • What were the methods used in the study?
    • Andrianov and Anishchenko used many softwares and other techniques to study the structure of this loop such as NMR spectroscopy and X-ray studies
  • Briefly state the result shown in each of the figures and tables.
    • Figure 1 shows the 3D structure of the V3 loops according to its best fit which shows a structural similarity between the 3
    • (rest of figure explanations seen above)

Presentation Powerpoint

References

Article:

  • Alexander M. Andrianov & Ivan V. Anishchenko (2009) Computational Model of the HIV-1 Subtype A V3 Loop: Study on the Conformational Mobility for Structure- Based Anti-AIDS Drug Design, Journal of Biomolecular Structure and Dynamics, 27:2, 179-193, DOI: 10.1080/07391102.2009.10507308
  • Presentation Guidelines

Acknowledgments

The work on the presentation was done together with Zach, Will, and Matt. We met Monday evening to finish and practice the powerpoint. While I worked with the people noted above, this individual journal entry was completed by me and not copied from another source. Mia Huddleston 17:21, 24 October 2016 (EDT)

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Bioinfomatics Lab: Fall 2016

Class Page: Bioinfomatics Laboratory, Fall 2016

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