Petsko G.A., Ringe, D., Protein Structure and Function 2004, figure 5-5, pg. 173.

Different ways to depict a protein structure

Wire diagram Ribbon diagramBall & stick of featured area

Space filling:van der Waals

Surface representation (GRASP image)

Blue: positiveRed: negative

• Enter Somethign

Primary Structure: Amino Acid Sequence

Model of HIV protease

http://mgl.scripps.edu/projects/tangible_models/movies

Tertiary Structure: An Example of an All-Alpha Protein, Hemoglobin Subunit

Rotated 90 Degrees

Tertiary Structure: An Example of an All-Beta Protein, Flu Virus Neuraminidase

1) Rotate 90 Degrees

Tertiary Structure: An Example of an Alpha/Beta Protein, Triose Phosphate

Isomerase

1) Rotate 90 Degrees

Tertiary Structure: An Example of an Alpha + Beta Protein, TATA Binding Protein

1) Rotate 90 Degrees

• Quaternary structure -- the relative arrangement of two or more individual polypeptide chains

• Protein assemblies can contain one type of polypeptide (homo-oligomer) or multiple types (hetero-oligomer)

• Example: Hemoglobin (oxygen carrier in blood)

• Hemoglobin is a hetero-tetramer composed of two alpha subunits and two beta subunits

From Tertiary to Quaternary Structure: Hemoglobin as an Example

Hemoglobin, Tertiary Structure

Hemoglobin, Quaternary Structure

Single Subunit

Tetrameric Hemoglobin

Proteins: Sequence --> Structure --> Function

Anfinsen Experiment: Denature ribonuclease (RNase)Remove denaturantAssay for RNase activity -- does the protein regain its 3-D structure and its enzymatic activity?

GroEL-GroES-(ADP)7 complexXu et al., 1997, Nature 388: 741

Molecular chaperones - Anfinsen cages for folding proteins

Clicker question: A good design for a stable folded protein is…

1) A polar/charged core with mostly nonpolar residues on the surface.

2) A nonpolar core with mostly polar/charged residues on the surface.

3) An even mix of polar/charged and nonpolar residues in the core and on the surface.

4) Fatty acids on the inside, ribonucleotides on the outside.

5) Ralph Lauren.

Clicker question: A good design for a stable folded protein is…

A) A polar/charged core with mostly nonpolar residues on the surface.

B) A nonpolar core with mostly polar/charged residues on the surface.

C) An even mix of polar/charged and nonpolar residues in the core and on the surface.

D) Fatty acids on the inside, ribonucleotides on the outside.

E) Ralph Lauren.

The Protein Folding Problem: the sequence of a protein cannot (yet) be used to predict its 3D

structure

?

Protein Structure Prediction

“Critical Assessment of techniques for Structure Prediction” (CASP 9) -- a competition

For more information or to enter, seehttp://predictioncenter.org/

Winners earn an automatic “A+” in Bi 1 (retroactively, if necessary)

Inverse Protein Folding ProblemInverse Protein Folding Problem

• Given a structure (or a functionality), identify an amino acid sequence whose fold will be that structure (exhibit that functionality).

• Can we make designer proteins with desired functions?

Foldit

• New Nature Video - Foldit: Biology for gamers - August 04, 2010

http://blogs.nature.com/news/thegreatbeyond/2010/08/new_nature_video_foldit_biolog.html

• From David Baker’s webpage: (http://depts.washington.edu/bakerpg/drupal/)Foldit is a revolutionary new computer game enabling you to contribute to important scientific research. Join this free online game and help us predict the folds of unsolved proteins as well as designing new proteins to cure diseases. We’re collecting data to find out if humans' pattern-recognition and puzzle-solving abilities make them more efficient than existing computer programs at pattern-folding tasks. If this turns out to be true, we can then teach human strategies to computers and fold proteins better than ever!