A very brief intro to proteins

Dr.Mikko Karttunen

Department of Chemistry

Waterloo Institute for Nanotechnology

University of Waterloo, Ontario, Canada

 


Web: www.softsimu.org

Email: mkarttu@gmail.com

Protein structure-function paradigm

Figure: Based on Mariana Ruiz Villarreal's illustration on Wikipedia

More on protein structure: [Nature Education]   [Molecular Biology of the Cell]   [Wikipedia]   [Amino acids]
Protein structure Nobel Prizes:   [Chemistry 1946]   [Chemistry 1962]   [Chemistry 1964]   [Chemistry 1972]   [Chemistry 2002]

Globular protein: Ubiquitin

Click to start. Rotate: mouse. Right-click: Controls                     console

PDB structure: 1UBQ     [Folding Funnel Diagrams: M. Karplus, Nat. Chem. Biol 7, 401 (2011)]
More on Ubiquitin: [Molecule of the month]   [UBQ on Wikipedia]   [Nobel Prize in Chemistry 2004]
Structural ensembles: IDP vs a 'traditional' protein.

IDPs: [Chem. Rev. 114, 6561 (2014)]   [Int. J. Biochem. & Cell Biol. 43, 1090 (2011)]   [Trend. Biochem. Sci. 37, 509, 2012]
IDPs in drug design: [Trends Biotech. 24, 435 (2006)]   [Curr. Op. Pharmacol. 10, 782 (2010)]

IDPs vs globular proteins

Typical amino acid compositions are different.

  • IDPs have more charged residues
  • more polar residues
  • more structure breaking residues (glycine & proline)
  • less aromatic content
  • less hydrophobic content


One reason for the dynamic behavior:

  • Lack of hydrophobic cores makes them more dynamic


Structure:

  • Lack of tertiary structure
  • There are elements of secondary structure
  • Linear motifs. Crucial for binding

p53 - "the Guardian of Genome"


     "Conformational biases of linear motifs",
     E. Cino, W.-Y. Choy, M. Karttunen,
     J. Phys. Chem. B 117, 15943 (2013).

Some general properties IDPs have

Advatages IDPs have:

  • Specificity without excessive binding strength
  • Fast, switch-like, binding
  • One-to-many signalling: Protein hubs


Hard to get experimental data:

  • There is in vitro evidence
  • There are in vivo hypotheses
  • Computational methods offer an alternative


Diseases:

  • Signalling related
  • Often cancer-related
  • Oxidative stress
  • Diabetes 2
  • Neurodegenerative diseases

p53, "the Guardian of Genome"

"Comparison of secondary structure formation using 10 different force fields in microsecond molecular dynamics simulations", Cino, Choy, Karttunen, J. Chem. Theory and Comput. 8, 2725 (2012)

Comparison of 10 different force fields

Comparison of secondary structure formation using 10 different force fields in microsecond molecular dynamics simulations, Cino, Choy, Karttunen, J. Chem. Theory and Comput. 8, 2725-2740 (2012)

Binding of disordered proteins to a protein hub, Cino, Killoran, Karttunen, Choy, Sci. Rep. 3, 2305 (2013).

Intrinsically Disordered Protein: Exoenzyme S

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