Zachary T. Goldstein Week 8: Difference between revisions

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Revision as of 23:13, 19 October 2016

Week 9 Journal Club Preparation

10 Definitions

  1. Glycosylation: The process of adding sugar units such as in the addition of glycan chains to proteins. An occurrence where a carbohydrate is added to a protein molecule, which can occur in the golgi apparatus. (http://www.biology-online.org/dictionary/Glycosylation)
  2. Virions: A single virus molecule complete with a coat. (http://www.biology-online.org/dictionary/Virions)
  3. Chemokine: A chemotactic cytokine released by cells to function in chemotaxis, inflammation, and angiogenesis. (http://www.biology-online.org/dictionary/Chemokine)
  4. Immunogenic: Refers to the ability of a substance (antigen) to induce an immune response. (http://www.biology-online.org/dictionary/Immunogenic)
  5. Annealing: The pairing of complementary dna or rna sequences, via hydrogenbonding, to form a double-stranded molecule. Mostoften used to describe the binding of a short primer or probe. (http://www.biology-online.org/dictionary/Anneal)
  6. Root mean square deviations(RMSD): A measure of difference between values; similarity. (http://www.oxfordreference.com/view/10.1093/acref/9780198529170.001.0001/acref-9780198529170-e-17481?rskey=Np5kZL&result=17301)
  7. Proteoglycans: A macromolecule that has a core protein attached covalently to one or more glycosaminoglycan chain (http://www.biology-online.org/dictionary/Proteoglycan)
  8. Dihedral angle: The inclination of two planes that meet at an edge (http://www.oxfordreference.com/view/10.1093/acref/9780198529170.001.0001/acref-9780198529170-e-5228?rskey=luZLnq&result=5102)
  9. Beta-turn: A short stretch of polypeptide chain that allows the main direction of the chain to change. It consists of four amino‐acid residues in which the CO group of residue n is hydrogen bonded to the NH group of residue n + 3. (http://www.oxfordreference.com/view/10.1093/acref/9780198529170.001.0001/acref-9780198529170-e-2081#)
  10. Asparagines: A crystalline amino acid found in proteins and in many plants; An amino acid that is a common part of many proteins. (http://www.biology-online.org/dictionary/Asparagine)

Outline

  1. Introduction
    • It is known that the HIV-1 virus enters human host cells through consecutive interactions with surface cell receptors and one of two chemokine co-receptors (CCR5 or CXCR4).
    • Binding to protein causes conformational change that reveals co-receptor binding site, also known as the V3 loop
    • This V3 loop plays a central role in virus biology and forms a good starting point for analyzing which point on the gene should be targeted for anti-AIDS drugs.
    • Most amino acids within the V3 loop are highly variable, but those found on the end terminals and along the immunogenic tip shows potential conservation and rigidity.
    • Understanding and developing a model of these rigid regions along the gene may provide researchers with a new target for drugs that is constant, which helps guide us through the constantly changing nature of the virus.
    • A good 3D model of these V3 regions could help map where exactly these targets exist within the gene.
    • Getting an exact model has been hard in the past due to a shortage of X-ray and NMR images around the region
    • Preferences of research are given to HIV subtype B found in North and South America, but computer models of subtype A were created to bridge gap between research data on two different subtypes.
    • Major steps taken in this study:
      • Low energy structures of the amino acid sequences contained in the subtype A V3 region were created, and a most probable confirmation was formed
      • Elements of secondary structures contained within the V3 region were characterized and analyzed throughout the various loops
      • Simulated structures were collated with each other and those formed using X-Ray crystallography and NMR spectroscopy to reveal commonalities throughout the structures.
      • Molecular dynamics were computed (MD) and rigid and flexible segments were defined within the region; findings were compared to previous studies
      • A model molecular docking between the V3 region and FKBP and CycA peptides was performed too observe the V3 regions that stay in contact with the ligands.
  2. Methods
    • Modeling 3D V3 Structures
      • Used knowledge of comparative modeling via Xray crystallography and NMR spectroscopy
      • MODELLER package used for comparative modeling
      • Subsets containing 10 best models were selected from each set for energy optimization and final refinement
      • Lowest energy confirmations were formed using AMBER and TINKER software
    • Identification of Secondary 3D Structures
      • Standard and non-standard Beta Turns were identified using classification methods from previous work
    • Comparison of 3D V3 Structures
      • Root Mean Square Deviations were taken in atomic units (cRMSD) for the entire V3 region and segments
      • Best similarity values fell below 2 Angstroms; smaller A means more similar structure
    • Molecular Dynamics Computations and Docking Simulations
      • GROMACS package were used for simulations
      • Every 10 ps geometric parameters of MD structure and energy data was recorded
      • Model docking used the Hex 4.5 program, 3D structures of 2 peptides were taken from previous studies
  3. Results
    • Figure 1
    • Figure 2
    • Figure 3
    • Figure 4
    • Figure 5
    • Figure 6
    • Figure 7
  4. Conclusions

Presentation Slides

Acknowledgements

References

BIOL368/F16

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All shared journals:

User: Zachary T. Goldstein

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