Week 8 Individual Journal William P Fuchs

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10 Previously Unknown Biological Terms

  1. glycosylated
  2. algorithm
  3. chemokine
  4. immunochemical
  5. crystallography
  6. simulated annealing
  7. dihedral angles
  8. proteoglycans
  9. tropism
  10. glycosyltransferase

Outline of Andrianov & Anishchenko's Paper

Link to Presentation and Link to Article

  1. Link to full article:PDF of paper
  2. Link to presentation slides: Journal Club Presentation


  • The virions enter the host cells through sequential interactions the CD4 cell surface receptors
  • After binding to the CD4 binding site, a 180 degree switch in the surface protein gp120 of the virus exposes the co-receptor binding site.
  • V3 loop of the glycoprotein gp120 is 35 residues long and highly variable
    • plays a central role in the virus biology in human invasion and immune system interaction.
    • is the head determinant for co-receptor binding.
    • HIV-1 V3 loop sequences are highly conserved.
  • Since the V3 region has a highly conserved nature it is a promising target for antiviral research. Of which prior research has partially covered.
    • Subsequently, V3 has become the focus of many developers of antiviral drugs and makes papers like this to be at the forefront of HIV-research.
  • Subtype A of HIV-1 is receives the short end of a disproportionate research preference to the HIV subtypes.
    • Paper seeks to abridge this complication by utilizing computer assisted modeling-reconstruction programs.
    • The V3 region was analyzed and the amino acids around the inflexible regions were identified and the structure-function analysis was performed in order to provide insight in regards to the anti-AIDS research commitment.
  • Several sequential steps were initiated:
    • The following steps were conducted through the usual paradigm of analysis when discussing the general quality and characteristics of proteins.
      • comparative modeling and simulated annealing was run.
      • from which the collection of the low-energy structures were generated to find a consensus amino acid sequence for the HIV-1 subtype A V3 loop.
      • the building blocks of the secondary V3 structures of the built conformations were characterized and recorded.
      • common structural motifs in the HIV-1 V3 loops were located.
      • after registering the intrinsic features of the SA-V3 loop,a molecular dynamics (MD) trajectory was derived from its static 3D structure. Then finding the structurally flexible and rigid V3 sections and comparing those findings with the prior obtained structures of the loop.
      • then to measure the masking effect that can occur with the interaction of the SA-V3 loop.
      • Other pertinent inner atomic interactions were evaluated to holistically research the loop structure.
  • From the analysis and data on molecular docking, it would seem that synthetic molecules copying the amino acid sequences of the (FKBP and CycA) peptides is pheasable in making V3-based anti-HIV-1 drug projects a reality and makes this study very impactful.


  • modeling of 3D structures for V3 was conducted in a sequential manner.
  • comparative modeling of 3D V3 structures derived from NMR spectroscopy vs. X-ray studies was conducted.
  • basis of templates and the consolidated V3 sequence used for subtype A came from the Los Alamos worldwide database.
  • Comparative modeling via: MODELLER package.
    • a special restraint requiring the closing of a disulfide bridge between the invariant residues Cys-1 and Cys-35 was preserved.
  • 100 models for each template was generated.
    • DOPE statistical potential within the MODELLER software evaluated quality of those models
  • 10 best models were selected>
    • these conformations were brought to collect local minimum that fulfilled the low-energy requirement of the models.
  • the models therein underwent the procedure of energy minimization in the AMBER force field.
    • via a simulated annealing algorithm
  • TINKER software used for molecular design.
    • PROCHECK procedure to check quality
  • Analysis of the φ, ψ values for the amino acids of the simulated models conducted.
    • further secondary protein structures analyzed
  • Compared the models and the similarity of their structures in the Cartesian space.
  • Values calculated for all V3 structures fragment sizes of 4-6 residues (Root-mean-square deviations).
    • CORESEARCH program initiated in computations
  • Molecular Dynamics computations
    • implemented by the GROMACS computer package
    • The starting 3D structure was presented in a way such that the radius of the Coulomb and Lennard-Jones potentials was fixed at 1.4 nm.
    • other physical tests run to evaluate the nature of each protein (i.e. pressure, motion)
  • Docking of molecules
    • Molecular docking of the HIV-1 subtype A V3 loop utilized by the Hex 4.5 program
      • presents feasible docking forms of pairs of protein and DNA molecules
    • The energy refinement of the dockings was performed via the minimize program of the TINKER software
    • SwissPdbViewer computer program analyzed the simulated over-molecular construct

Results and Discussion

  • The arrived 4 models differed from a Cartesian interpretation
    • dissimilar in the geometric space
  • its central portion 15-19 of the models shows a connection with historical interpretations according to which these V3 stretches play a very important role in AIDS pathogenesis.
  • There are many key sites that have key interactions with the host cell and there are clear relationships between the models of the V3 loops and classical function i.e. defense against antibodies.
  • In regards to the V3 sequence, special attention to Gly-Pro-Gly which is

virtually fulfilled in all of the known primary structures of the HIV-1 principal neutralizing determinant

  • Figure 1: displays the best fitting conformations of the 3D models which highlights the sequence and geometric similarities to the Cartesian space and their respective cRMSDs.
  • structural conservatism
    • comparative analysis of the simulated structures in terms of the dihedral angles indicates that it is conserving the conformations of individual V3 residues.
  • late amino acid substitutions about the V3 positions during virus pathogenesis cause HIV-1 to switch from CCR5- to CXCR4-dependent isolates.
  • further Angstrom values derived.
    • it was found that the close spatial folds within the V3 segments are formed using the different local minima of the residues.
    • also there is evidence supporting that there the highly conserved amino acid residues within the HIV-1 V3 variation loops.
      • subsequently, V3 sites will retain their 3D backbone shapes in viral isolates and other different environments.
  • Figure 2: displays the most likely 3D structure of the HIV-1 subtype A V3 loop derived from the various computations and quality checks performed in the study.
  • Figure 3: presents the likely secondary structures of the simulated conformations of the V3 loop.
  • study claims that the generated model shows the best interactions and structure of the V3 loop in respect to the various secondary structure predictions and gp120 positioning (supported by Molecular dynamics as well).
    • furthermore, the static V3 structures observed in various HIV-1 isolates within different environments: inspection of the MDs trajectory created for the SA-V3 loop within 10 ns time domain is the evidence of the high flexibility of the 3D structure becoming realized in both: Cartesian coordinates and dihedral angles.
  • Figure 4: presents cRMSD values (Å) as a function of time between all MD conformations.
    • shows that close spatial folds within these segments may be composed of different local minima of their amino acids which is important to note.
  • Figure 5: conformational V3 "freedom"h through Graphics 1-11 show the mean values of all the cRMSD for the V3 segments.
    • its longer central sites were shown to preserve their 3D folds within the prescribed computational time constraint.
    • the starting end of the V3 loop containing the amino acids of the N and C terminus exhibited higher conformation mobility which addresses its mobility within the Cartesian space.
  • Figure 6: exhibits the more dynamic behavior of the V3 loop in respect to geometric space and dihedral angles.
    • it is concluded that the individual residues around the center of the V3 loop conserve their concensus chain torsional angles
    • this section of the V3 segment determines extensively the immunogenicity of gp120.
    • integral in the co-receptor usage complex.
    • single V3 amino acids didn't undergo the stark reorganization at the time of simulations.
  • The impact of this study yields that joint analysis of static and dynamic models exposes the weak links which lines up search for potential broad anti-AIDS therapeutic agents.
  • Figure 7: Structural complexes of models and residues.


I worked with Mia Huddleston, Zachary T Goldstein and Matthew Oki for the construction of the presentation, we met out of class for 3-4 hours and communicated over social media. -While I worked with the people noted above, this individual journal entry was completed by me and not copied from another source. William P Fuchs 22:26, 24 October 2016 (EDT)


  • Andrianov, A. M., & Anishchenko, I. V. (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. http://dx.doi.org/10.1080/07391102.2009.10507308


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Useful Links

  1. Bio Class Page
  2. BIOL368/F16:People
  3. Will Fuchs
  4. Link to LMU: http://www.lmu.edu/