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Related Concept Videos

Phosphorylation01:02

Phosphorylation

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The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
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Intrinsically Disordered Proteins02:18

Intrinsically Disordered Proteins

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Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be...
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Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

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Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
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Protein Folding01:25

Protein Folding

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Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
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Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
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Conservation of Protein Domains Over Different Proteins02:26

Conservation of Protein Domains Over Different Proteins

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Protein domains are small structurally independent units that are part of a single amino acid chain.  Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...
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Related Experiment Video

Updated: Jul 12, 2025

Nuclear Magnetic Resonance Spectroscopy for the Identification of Multiple Phosphorylations of Intrinsically Disordered Proteins
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Nuclear Magnetic Resonance Spectroscopy for the Identification of Multiple Phosphorylations of Intrinsically Disordered Proteins

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Machine Learning Subtle Conformational Change due to Phosphorylation in Intrinsically Disordered Proteins.

Subinoy Adhikari1, Jagannath Mondal1

  • 1Tata Institute of Fundamental Research, Hyderabad 500046, India.

The Journal of Physical Chemistry. B
|October 31, 2023
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Phosphorylation subtly alters intrinsically disordered proteins (IDPs) by changing hydrogen bonds and interactions, revealing hidden conformational changes not seen in experimental measurements. Machine learning uncovers these phosphorylation-induced effects in yeast proteins.

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Nuclear Magnetic Resonance Spectroscopy for the Identification of Multiple Phosphorylations of Intrinsically Disordered Proteins
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Area of Science:

  • Biochemistry
  • Computational Biology
  • Structural Biology

Background:

  • Phosphorylation significantly impacts intrinsically disordered proteins/regions (IDPs/IDRs), influencing critical biological functions like cell signaling and protein dynamics.
  • Experimental studies on yeast IDPs (Ash1 and Sic1) show minimal changes in average conformational properties upon phosphorylation.
  • Understanding phosphorylation's role in IDP function is crucial but challenging due to experimental limitations.

Purpose of the Study:

  • To investigate subtle conformational changes in phosphorylated IDPs using advanced computational methods.
  • To compare the effects of phosphorylation on the conformational ensembles of Ash1 and Sic1 IDPs from *Saccharomyces cerevisiae*.
  • To elucidate the molecular mechanisms by which phosphorylation modulates IDP behavior.

Main Methods:

  • Utilized multi-microsecond molecular dynamics (MD) simulations of wild-type and phosphorylated IDPs.
  • Developed a Markov state model (MSM) based on autoencoder-derived latent-space dimensions.
  • Analyzed structural features including contact maps, secondary structure, torsion angles, hydrogen bonding, and non-bonded interactions.

Main Results:

  • Machine learning dissection revealed key similarities and differences in conformational states upon phosphorylation.
  • Phosphorylation increased hydrogen bonds, altered backbone-side chain hydrogen bonding patterns, and introduced salt bridges.
  • Observed a loss of cation-π interactions, increased long-range hydrophobic contacts, and enhanced water-protein interactions.

Conclusions:

  • Machine learning combined with MD simulations can effectively characterize phosphorylation-induced conformational changes in IDPs.
  • Phosphorylation induces significant, albeit subtle, alterations in IDP structure and dynamics not easily detected by bulk experimental measurements.
  • These findings provide crucial insights into the functional consequences of IDP phosphorylation.