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How do conformational changes take place?

  1. Jul 10, 2017 #1
    Hi everyone,

    I don't understand how ATP binding, hydrolysis, and dissociation actually causes movement within a molecule, say a protein. I'd like to understand this in terms of seeing ATP and the protein themselves as molecular orbitals and changes in energy states of electrons.
    Take this example: http://www.nature.com/nm/journal/v18/n10/fig_tab/nm.2924_F5.html
    ATP binds myosin, causing a converter domain to rotate and a switch loop to close, forming a system of hydrogen bonds and some more rotations occur, leading to ATP hydrolysis. With ADP + Pi bound, myosin now binds actin, after which Pi dissociates, causing the lever arm to move, et cetera et cetera.
    I understand ATP hydrolysis provides the (thermal?) energy required for these changes to take place, but I have a gap in knowledge how. It just makes the electrons of the myosin vibrate more? And how are the physical movements taking place?

    Many thanks
     
  2. jcsd
  3. Jul 10, 2017 #2

    Ygggdrasil

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    From a thermodynamic point of view, ATP hydrolysis makes one step of the thermodynamic cycle irreversible so that the molecule will traverse the cycle only in one direction.

    From a mechanical point of view, ATP generally binds to motor proteins in a pocket in the interior of the protein. The different states associated with ATP hydrolysis (ATP --> ADP + Pi --> ADP) will have very different shapes that can cause changes to the shape of the pocket surrounding the nucleotide. For example, after ATP hydrolysis, you have the beta and gamma phosphate groups moving apart, which can induce changes to the surrounding protein, as can the reduction in size of the pocket that occurs when the phoshpate leaves. These changes to the shape of the nucleotide binding pocket can propagate throughout the protein, causing larger conformational changes throughout the protein. The nucleotide binding pockets of ATPases often occur at the interface between different subdomains of the protein, so changes to the shape of the nucleotide binding pocket will greatly change the quaternary structure of the protein.

    Aside from the chemical catalysis of the ATP hydrolysis reaction, I believe most of the changes are essentially mechanical and do not require understanding the electronic states of the atoms in the protein.
     
  4. Jul 13, 2017 #3
    When a ligand binds protein, say diacylglycerol binding PKA, then the molecular orbitals of the PKA must change, either in character or shape, correct?
    Because the shape of PKA changes, so thus its MO must be changing.
    Why is this? Is it simple electron (orbital) repulsion? When a ligand binds, hydrogen bonds (and van der waals and ionic bonds?) within the protein, in favour of new ones with the incoming ligand. So basically electrons are moving, from being shared internally to being shared with a ligand?
     
  5. Jul 13, 2017 #4
    One thing to keep in mind is that proteins are not static entities - the level of ordering and rigidity can vary dramatically, with some proteins being like rocks, while others can be unstructured except in certain conditions. While I'm not super familiar with that particular example with PKA, I do recall a nice study from a while back looking at PKA interacting with a nucleotide and a protein substrate, where nucleotide binding shifted the population of open and closed states of the PKA enzyme which facilitated substrate binding and catalysis.
     
  6. Jul 14, 2017 #5

    Ygggdrasil

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    A good way to think about protein conformational dynamics is through energy landscape theory. There is a multidimensional energy landscape describing the thermodynamic stability of the different protein conformations, and this energy landscape can change upon binding to the ligand. These energy landscapes account for electrostatic, van der Waal, and other intermolecular interactions between atoms in the protein and in the ligand.

    Here is a nice review article discussing how conformational change influences intermolecular interactions from the perspective of energy landscape theory: https://www.nature.com/nchembio/journal/v5/n11/full/nchembio.232.html
     
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