Mia Huddleston Week 8

Preparation for Week 9 Journal Club

10 Biological Terms from Article

1. Glycoprotein:
2. Virions:
3. Entry inhibitors:
4. Immunochemical properties:
5. Annealing:
6. Beta-turns:
7. Dihedrals:
8. Molecular docking:
9. Pentapeptide:
10. Central proline:

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)

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

Acknowledgments

While I worked with the people noted above, this individual journal entry was completed by me and not copied from another source.

Useful links

User Page: Mia Huddleston

Bioinfomatics Lab: Fall 2016

Class Page: Bioinfomatics Laboratory, Fall 2016

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