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So does flexible mean that there may be different amino acids in a portion of the peptide? From my understanding, when flexibility is discussed in terms of prot

So does flexible mean that there may be different amino acids in a portion of the peptide? From my understanding, when flexibility is discussed in terms of proteins we're talking about rigid vs flexible side chains which can move or rotate along specific bonds So for the intrinsically disordered ones, are you mainly talking about the secondary or tertiary structures? My assumption based on your statement is that we're keeping the same primary structure (order of amino acids) but they don't have many (if any at all) intermolecular interactions? Would it be safe to assume that you're referring to shorter polypeptide rather than large proteins?

dekhn 5y ago
in disordered proteins, there is no permanent tertiary structure. they may have some secondary structure, but the relations of those structural elements can change in time. It does not mean the seuqence has variation in it.
- alan-hn 5y ago
  Does this mean that they have multiple conformational states with similar energies that are easy for it to transition between? How different are the states and is this how the protein normally does its proteiny stuff?
  - dekhn 5y ago
    yes, I would say that intrisnically disordered proteins adopt something like an unfolded state, which is to say that they can visit a wide range of structures that are at similar energy levels, all of which are accessible at ~room temp. I can't really answer in more detail because all the ID proteins are fairly different an dhow they do their job is hard to understand compared to stable static "rocks" like enzyymes.
    - throwawaybio3 5y ago
      Enzymes aren't stable and static -- usually in their active site they have significant conformational changes that enable catalysis of the relevant chemical reaction. It's quite a problem that we don't have general robust ways of directly elucidating those transient structures, a lot of our understanding of catalysis is still held back or slow-evolving because we can only use indirect and cumbersome methods (like isotopic mutation + laser IR) I would consider most enzymes to be intrinsically disordered at their active sites.
      - dekhn 5y ago
        No enzymes are not intrinsically disordered at their active sites. They are highly ordered. Most enzymes don't undergo large changes- they accept a molecule, do their business, and release it. You're thinking of other proteins like motor proteins which under go large, controlled conformational changes. The active site is structured to stabilize the transition state of the affected molecule and move it from one state to the next in the chemical reaction. That requires very specific shapes and correlated changes. But of course, this being biology, you can remove all 3 active site residues in a serine protease catalytic triad, and still see proteolysis because the protein, when it binds the substrate, forces the subtrate into its transition pathway. People have been working on these things for quite some time- I saw talks about time-resolved crystallography of active sites, and while they say "significant structure changes", they really only mean localized breathing-like motions, not massive rotations of entire domains.
  - f38zf5vdt 5y ago
    Yes, many proteins have transitional global arrangements that it traverses as it meets some goal. For example, kinesin and dynein walk along microtubules in a way where we could never perfectly characterize the intermediary states since it's effectively a motor with free rotation around certain elements. A lot of crystallography is focused on enzymatic reactions where you bind a ligand that sits there for the sake of introducing some conformation that you can study. The ligands generally approximate the natural substrate at either the beginning, end, or some intermediate step in enzyme catalyzed synthesis.
- panabee 5y ago
  is it possible to identify which proteins are intrinsically disordered based on amino acid sequence alone (or even base sequence)? put another way, is it possible to a priori determine if a protein is ID or ordered? for instance, you said enzymes are highly ordered. is this based on experimental observations (which could later be wrong if imaging techniques improve) or is there some principle that allows us to treat this as a fact? thanks in advance for your time.
  - flobosg 5y ago
    > is it possible to a priori determine if a protein is ID or ordered? There’s software that attempts to predict intrinsic disorder based on sequence alone, but in general, in the absence of homolog (evolutionarily related) proteins with known structure you would still need to check experimentally for disorder. EDIT: > if the goal is to reliably assess certain viral proteins as ID or ordered, experimental methods are the only methods for achieving this? If you don’t find homologs with solved structures, experimental characterization is the way to go.
    - panabee 5y ago
      thanks for the explanation. to clarify, if the goal is to reliably assess certain viral proteins as ID or ordered, are experimental methods the only methods for achieving this?
    - deleted 5y ago
      [deleted]
  - dekhn 5y ago
    A priori? No. Typically this would be determined by synthesizing or expressing the protein of interest and then using something like CD (circular dichroism). There is an absolutely enormous amount of experimental data about enzyme structure, but frankly I think the simplest is to just understand that the modern ideas about the reversible protein folding process came from ribonuclease, a protein that cuts RNA: https://en.wikipedia.org/wiki/Anfinsen%27s_dogma https://en.wikipedia.org/wiki/Anfinsen%27s_dogma There may also be intrinsically disorderd enzymes, I'm not really sure how they would work, but of course, in biology, there's always a weird example that violates normal expectations because evolution once randomly tried somethign a billion years ago and got stuck with it.

dekhn 5y ago

in disordered proteins, there is no permanent tertiary structure. they may have some secondary structure, but the relations of those structural elements can change in time. It does not mean the seuqence has variation in it.

alan-hn 5y ago
Does this mean that they have multiple conformational states with similar energies that are easy for it to transition between? How different are the states and is this how the protein normally does its proteiny stuff?
- dekhn 5y ago
  yes, I would say that intrisnically disordered proteins adopt something like an unfolded state, which is to say that they can visit a wide range of structures that are at similar energy levels, all of which are accessible at ~room temp. I can't really answer in more detail because all the ID proteins are fairly different an dhow they do their job is hard to understand compared to stable static "rocks" like enzyymes.
  - throwawaybio3 5y ago
    Enzymes aren't stable and static -- usually in their active site they have significant conformational changes that enable catalysis of the relevant chemical reaction. It's quite a problem that we don't have general robust ways of directly elucidating those transient structures, a lot of our understanding of catalysis is still held back or slow-evolving because we can only use indirect and cumbersome methods (like isotopic mutation + laser IR) I would consider most enzymes to be intrinsically disordered at their active sites.
    - dekhn 5y ago
      No enzymes are not intrinsically disordered at their active sites. They are highly ordered. Most enzymes don't undergo large changes- they accept a molecule, do their business, and release it. You're thinking of other proteins like motor proteins which under go large, controlled conformational changes. The active site is structured to stabilize the transition state of the affected molecule and move it from one state to the next in the chemical reaction. That requires very specific shapes and correlated changes. But of course, this being biology, you can remove all 3 active site residues in a serine protease catalytic triad, and still see proteolysis because the protein, when it binds the substrate, forces the subtrate into its transition pathway. People have been working on these things for quite some time- I saw talks about time-resolved crystallography of active sites, and while they say "significant structure changes", they really only mean localized breathing-like motions, not massive rotations of entire domains.
- f38zf5vdt 5y ago
  Yes, many proteins have transitional global arrangements that it traverses as it meets some goal. For example, kinesin and dynein walk along microtubules in a way where we could never perfectly characterize the intermediary states since it's effectively a motor with free rotation around certain elements. A lot of crystallography is focused on enzymatic reactions where you bind a ligand that sits there for the sake of introducing some conformation that you can study. The ligands generally approximate the natural substrate at either the beginning, end, or some intermediate step in enzyme catalyzed synthesis.
panabee 5y ago
is it possible to identify which proteins are intrinsically disordered based on amino acid sequence alone (or even base sequence)? put another way, is it possible to a priori determine if a protein is ID or ordered? for instance, you said enzymes are highly ordered. is this based on experimental observations (which could later be wrong if imaging techniques improve) or is there some principle that allows us to treat this as a fact? thanks in advance for your time.
- flobosg 5y ago
  > is it possible to a priori determine if a protein is ID or ordered? There’s software that attempts to predict intrinsic disorder based on sequence alone, but in general, in the absence of homolog (evolutionarily related) proteins with known structure you would still need to check experimentally for disorder. EDIT: > if the goal is to reliably assess certain viral proteins as ID or ordered, experimental methods are the only methods for achieving this? If you don’t find homologs with solved structures, experimental characterization is the way to go.
  - panabee 5y ago
    thanks for the explanation. to clarify, if the goal is to reliably assess certain viral proteins as ID or ordered, are experimental methods the only methods for achieving this?
  - deleted 5y ago
    [deleted]
- dekhn 5y ago
  A priori? No. Typically this would be determined by synthesizing or expressing the protein of interest and then using something like CD (circular dichroism). There is an absolutely enormous amount of experimental data about enzyme structure, but frankly I think the simplest is to just understand that the modern ideas about the reversible protein folding process came from ribonuclease, a protein that cuts RNA: https://en.wikipedia.org/wiki/Anfinsen%27s_dogma https://en.wikipedia.org/wiki/Anfinsen%27s_dogma There may also be intrinsically disorderd enzymes, I'm not really sure how they would work, but of course, in biology, there's always a weird example that violates normal expectations because evolution once randomly tried somethign a billion years ago and got stuck with it.