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Protein structure basis - Understand 3D models

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  • Protein structure basis - Understand 3D models

    Hello all,

    Now that we explore how the genetic code is the recipe to build all protein and that this is this major life process that virus target while they try to infect us... Majors constituents of life and the chain of biochemical influence

    ... now that we see what are the generals mechanism that allow Influenza to enter our cells via the hemmagglutininn... How hemaglutinin work

    we could try to understand what exactly is responsible for the ability of the recepror binding receptor (RBS) to infect avian ( mostly a2,3 cells ) or human cells ( mostly a2,6 cells ).

    Many individuals "mutation" have been spotted to explain why this change happen...
    Genomic Signatures of Human versus Avian Influenza A Viruses - Mutations to check out

    Evidence of an absence: the genetic origins of the 1918 pandemic influenza virus.

    Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals.

    But this "singles point amino acid mutation" do not explain it all.
    Every sub-class of hemaglutinnin seem to have is own way to step species and it is hard to extrapolate what could be the recquired H5 change to allow this to happen.

    The reallity is that there is also a strong 3D shape variable that is responsible for that change and "cross-species" capability.

    There is also many other change recquire outside of the HA gene but the current H5 do not seen to have problem to replicate in our cells.
    The last step seem to be "efficient airborn specificity" and this trait is beleive to be controlled by change in the hemaglutinnin.

    So...

    In order to understand the importance of the general 3 dimentionnal shape for a protein activity and for the RBS specificity, I will here try to explain some basic protein structural concepts.

    After this you will be more "equipped" to fully understand the theoriticals computer models I exposed in that thread...
    http://www.flutrackers.com/forum/showthread.php?t=9645

  • #2
    Re: Protein structure basis - Understand 3D models

    Proteins ( hemagglutinnin is one of them ) is a large group of molecule that have the common caracteristic of being made of amino acids.

    In fact a protein is a polymers of aminoacid who are the individuals "brick" that build them.

    From Wikipedia, the free encyclopedia

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    <!-- start content -->
    The general structure of an amino acid molecule, with the amine group on the left and the carboxylic acid group on the right. The R group is dependent on the amino acid.


    In chemistry, an amino acid is any molecule that contains both amine and carboxylic acid functional groups. In biochemistry, this shorter and more general term is frequently used to refer to alpha amino acids: those amino acids in which the amino and carboxylate functionalities are attached to the same carbon, the so-called α?carbon.
    An amino acid residue is what is left of an amino acid once a molecule of water has been lost (an H<sup>+</sup> from the nitrogenous side and an OH<sup>-</sup> from the carboxylic side) in the formation of a peptide bond.
    Just as the letters of the alphabet can be combined in different ways to form an endless variety of words, amino acids can be linked together in varying sequences to form a huge variety of proteins. The unique shape of each protein determines its function in the body.

    There is 20 of them.

    All have the same general structure


    All are similar except for the R wich reptesent the side chain.
    Each differents aminoacids will have a specific side shain.
    This side chain will be responsible for the property the aminoacod will bring into the protein.
    Some are positively charge;
    Some are negatively charge;
    Some can built chemicals link with others molecules;
    Some are hydrophobic;
    Some are hydrophilic;
    Each one will have a different impact on the PH around them.



    A protein can be understood like a pearl neck-lace, each pearl being a amino acid.
    Theses amono acid will be linked together with what is called a peptide bond. This bond is produce by the ribosome when the protein is translated from the RNA code.



    This peptide bond have the perticularity of being "hard" , wich mean they will not allow twist or rotation at that place.



    The blue rectangular here represent the atoms that must be on the same plane.
    But rotation is allow around the C atoms on each side of this plane.



    So this succession of fixed and rotative chemical link in the chain allow the comparison to a pearl neck-lace where each pearl represent an amino acid.

    But each "pearl" will have a different form and property.



    This succession of single amino acid is called the primary structure of the protein.

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    • #3
      Re: Protein structure basis - Understand 3D models

      This primary structure is often arrange in space in known regular structure called secondary structure.

      The two mostly seen are the alpha helix oftenly represent like a coil.



      And the so called beta sheet oftenly represent like succession of bold arrow.



      All thoses "secondary structure are arrange in the space in a way to produce the complete 3D structure of a single sub-unit of a protein in a way they can be represented like that.
      This is called the tertiary structure:

      Next is to come the H5 tertiary structure of the HA1 subunit....

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      • #4
        Re: Protein structure basis - Understand 3D models

        Here is to the left the tertiary structure of a Indonesian RESRRKKR virus HA1
        I modell it using the services and program describe in that thread
        http://www.flutrackers.com/forum/showthread.php?t=9645

        Click image for larger version

Name:	H5 tertiary structure.bmp
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ID:	647792Click image for larger version

Name:	H5 complete atom.bmp
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Size:	425.0 KB
ID:	647793


        The part to the top is wich look like a phone microphone flat part is the RBS region and the part to the bottom like a tail is the cleavage site.

        HA2 is nor represented

        To the right is the same but with all atoms represented.

        We must always remember that this this the most stable shape that is represented and that any PH, Salinity and temperature change can change the 3D shape in many way.
        Some part are mobile some others are more stables.
        This is really like a very very small scramble coil that can cork in many way.

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        • #5
          Re: Protein structure basis - Understand 3D models

          Here is again the same in the same angle with a matematical representation of the electronic surface that the general molecule will have.

          Blue represent positives chaged area
          Red represent negativeli charges area.

          Click image for larger version

Name:	H5 complete surface.bmp
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ID:	647794

          I think now you should understand a little more what are the models exposed there
          Hemaglutinnin 3D modelling - H5 models exposed here

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          • #6
            Re: Protein structure basis - Understand 3D models

            The models presented in the other thread are models generated by mathematical calculation of the most stable conformation based on a similar X-ray structure analysys.

            So they are computer extrapolation.

            One of the direct real data modelisation of a H5 Hemaglutinnin haved been deposit in the NCBI database by

            <table style="width: 505px; height: 181px;"><tbody><tr><td class="H4" align="right" valign="top">Reference: </td> <td class="TEXT">Stevens J, Blixt O, Tumpey TM, Taubenberger JK, Paulson JC, Wilson IA Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus Science v312, p.404-410</td> </tr> <tr><td class="H4" align="right" nowrap="1" valign="top">Description: </td> <td class="text">Crystal Structure Of A H5n1 Influenza Virus Hemagglutinin.</td> </tr> <tr><td class="H4" align="right" nowrap="nowrap" valign="top">Deposition: </td> <td class="TEXT">2006/1/3 </td> </tr> <tr id="descrdep" style="display: none;"><td>
            </td> <td><table> <tbody><tr><td class="SMALL1" align="right" valign="top">Author:
            </td> <td class="SMALL1">Stevens J, Wilson IA
            </td> </tr> </tbody></table>
            </td> </tr> <tr><td class="H4" align="right" valign="top">Taxonomy: </td> <td class="text">Influenza A virus</td></tr></tbody></table>

            Here is from this model

            The HA1 model
            Click image for larger version

Name:	HA1.bmp
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ID:	647796

            The HA1 + the HA2 subunit
            Click image for larger version

Name:	HA1 + HA2.bmp
Views:	1
Size:	204.5 KB
ID:	647797The Ha2 subunit is the part that is root in the virus's enveloppe the "cleavage" at the cleavage site separate theses two part

            The way they are assemble in 3-mers the way they are on the surface of the virus.
            This is call the quaternary structure...
            Click image for larger version

Name:	HA trimer.bmp
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Size:	258.0 KB
ID:	647798The lower part is anchored in the virus's enveloppe

            This same tri-mers saw from the top where the hole youn see in the RBS, the 3 internal sides of this hole is the face I presented in the other thread
            Click image for larger version

Name:	HA trimer top.bmp
Views:	1
Size:	129.0 KB
ID:	647799You can see the tree part facing the center

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            • #7
              Re: Protein structure basis - Understand 3D models

              To add the overall complexity, some aminoacid can be "glycolised" wich mean that they can attatch with a chemical bond a complex sugar molecule.

              So, imagine that you can attatch sugar molecules at some place to the surface of that molecule...

              The a2,3 and a2,6 glycans receptors on the surface of our cells must stick in the RBS of this complex molecule.

              For that, the right aminoacid charged with the right charge must be placed in the right angle at the right place to allow the RBS to be effective.

              There is many way to skin a cat ( ) yes it is and the 3D shape is fundamental to allow this.

              So, how H5 could effectively jump to our species
              Well, that's a really complex question .

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