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Chapter 6 The Three-Dimensional Structure of Proteins. Homework: 1, 9,12 ,. Proteins: Higher Orders of Structure . The structural variety of human proteins reflects the sophistication and diversity of their biologic role

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proteins higher orders of structure
Proteins: Higher Orders of Structure
  • The structural variety of human proteins reflects the sophistication and diversity of their biologic role
  • The maturity of a newly synthesized polypeptide into a biologically active protein requires that it be folded into a specific 3-D arrangement or conformation
conformation vs configuration
Conformation vs. Configuration
  • Configuration deals with the arrangement of specific bonds about individual atoms
  • Conformation refers to the spatial relationship of every atom of a molecule
  • Proteins were initially characterized by their gross characteristics
initial characterizations
Initial Characterizations
  • Soluble proteins
  • Globular proteins
  • Fibrous proteins
  • Lipoproteins
  • Glycoproteins
  • Metalloproteins
currently classification and folding
Currently classification and Folding
  • Now, proteins are classified based on similarity or Homology, of residue sequence and structure
  • Typical proteins could have >1050 possible conformations
  • But since they fold as they form, it is easier to achieve biologically active conformation
orders of protein structure
Orders of protein structure
  • Primary Structure, 1o
  • Secondary Structure, 2o
  • Tertiary Structure, 3o
  • Quaternary Structure, 4o
secondary structure
Secondary Structure
  • The number of possible secondary structures is restricted
  • The is only free rotation about 2 of the 3 bonds in the backbone
  • Phi angle
  • Psi angle
alpha helix
Alpha Helix
  • Figure 6.3a, page 164
  • Both Phi and Psi angles are defined as well as distance it rises per turn
  • Complete turn averages 3.6 residues
  • R groups face outwards
  • Mostly only righthandeda-Helix seen in nature due to mostly L-amino acids used!
stabilizing the helix
Stabilizing the helix
  • H-bonds
  • van der Waals in core
  • Proline is only found in 1st turn. Why?
  • When present elsewhere, disrupts helix and forms a bend
  • Most hydrophobic R groups are on one side and hydrophilic on the other. Effect?
the beta sheet
The Beta Sheet
  • As opposed to the helix, the amino acids are extended to form a zigzag or pleated pattern
  • The R groups alternate up/down for a joining residues
  • Stabilized by H-bonds, but without proximity
  • Figure 6.3b, page 165
types of beta sheets
Types of Beta Sheets
  • Parallel- adjacent segments proceed in same directions as far as amino to carboxyl
  • Antiparallel- Adjacent chains proceed in opposite directions, as in 6.3b.
  • Most have a right hand twist, they are not flat
  • Depictions, see figure 6.16, page 179
loops and bends
Loops and Bends
  • Approximately half the residues in a protein are in either a helix or beta sheet.
  • The other half are in less ordered conformations such as Loops, Bends, etc.
  • Turns and Bends are short segments that connect secondary structures
beta turn
Beta Turn
  • Beta turns involve four Amino Acid residues with the 1st residue H-bonded to the 4th residue resulting in a tight, 180 degree turn
  • Fig 6.18 page 181
  • Proline and Glycine are often present in beta turns. Why?
  • Loops are regions that contain more AA residues than minimally required to connect adjacent secondary structures
  • Although they have no set conformation, they do serve key biological roles
  • There are some conformations that are secondary structures interacting, but not enough to be termed a tertiary
super secondary structures
Super Secondary Structures
  • Helix-Loop-Helix
    • Provide the oligonucleotide-binding portion of DNA-binding proteins such as repressors and transcription factors
back to loops
Back to Loops
  • Loops are mainly found on the exterior portion of a protein.
    • Exposed to solvent
    • Readily accessible sites for recognition and binding
  • While the structure may be irregular, they still exist in specific conformations
  • Conformations are held together by H-bonds, salt bridges, and hydrophobic interactions
tertiary and quaternary structure
Tertiary and Quaternary Structure
  • 3o refers to the entire 3D conformation of the protein
  • Domain-a section of protein structure sufficient to perform a particular chemical or physical task such as binding of a substrate or ligand
  • Proteins may have one or more domains.
  • Fig 6.27 page 192
tertiary and quaternary structure1
Tertiary and Quaternary Structure
  • In some cases, proteins are assembled from more than one polypeptide or protomer
  • Quaternary structure defines both the composition and spatial relations between these multiple chains.
  • Monomeric proteins consists of one chain
  • Dimeric proteins consists of two chains
  • For Dimeric and above, there are different kinds:
    • Homodimers-contain two copies of same chain
    • Heterodimers- contain two different chains
  • Greek letters are used to identify the different chains and subscripts indicate the number of each unit.
stability of 3 o and 4 o structures
Stability of 3o and 4o structures
  • Primarily stabilized by non-covalent forces
  • Hydrophobic interactions-
  • H-Bonds
  • Salt-bridges
  • Etc
  • Think Velcro!!!
determining 3d structure
Determining 3D Structure
  • Two main techniques:
  • X-Ray crystallography
  • NMR Spectroscopy
x ray chrystallography
X-Ray Chrystallography
  • Key is to get a good crystal!!!
  • Then bombard the crystal with x-rays and acquire a diffraction pattern
  • The diffraction pattern, along with the primary structure can be used to deduce the 3D structure.
x ray chrystallography1
X-Ray Chrystallography
  • Computers are getting better and better at interpreting X-ray diffraction patterns
  • Major stumbling block remains the requirement of inducing highly purified samples of the protein to crystallize
  • Several lines of evidence, including the ability of some crystallized enzymes to catalyze chemical reactions, indicate that the majority of the structures determined by X-ray crystallography represent the structures of proteins in free solution.
nmr spectroscopy
NMR Spectroscopy
  • Many common nuclei can be “seen” by NMR
  • Chemical shifts depend on the nuclei, what functional group it is in, and neighboring NMR nuclei
2 d nmr
  • Shows which nuclei are near each other.
protein folding
Protein Folding
  • We have said the number of possible conformations of even small peptides is very large
  • Thermodynamics dictate the formation of the conformation
  • The desired conformation is usually energetically favored
protein folding1
Protein Folding
  • Even with this energetically favored situation, it would take billions of years for a protein to explore all possible conformations to find the favored state
  • So folding has to take place in some sort of guided environment
  • First, as protein leaves the ribosome, short segments fold into secondary structures which are directed by the primary sequence
protein folding2
Protein Folding
  • Second, the aqueous environment of the cell drives all hydrophobic side groups to the middle of the protein creating a molten globule
  • Regions of secondary structure rearrange to form the mature conformation.
  • While this process is ordered, it is not rigid
  • In vivo- in the cell
  • In vitro- in test tube
  • Denatured- unfolding of a protein
  • Aggregates- disordered complexes of unfolded or partially unfolded polypeptides held together by hydrophobic interactions
  • Chaperone proteins help fold over half the proteins in mammals
  • They work by covering up hydrophobic groups, shielding them from the aqueous environment, thus preventing aggregation
  • Chaperons can also rescue misfolded proteins.
higher orders
Higher Orders
  • Disulfide bonds help stabilize tertiary and quaternary structures even though they are non-specific.
  • The protein disulfide isomerase is present to continually break and reform disulfide bonds.
x proline peptide bonds
X-Proline Peptide Bonds
  • All X-proline peptide bonds-where X represents any residue-are synthesized in the trans configuration.
  • However, of the X-Proline bonds of mature proteins, approximately 6% are cis.
  • The cis configuration is particularly common in Beta-turns.
  • Isomerization from trans to cis is catalyzed by the enzyme proline-cis,trans-isomerase.
alzheimer s disease
Alzheimer’s Disease
  • Refolding or misfolding of protein endogenous to human brain tissue, b-amyloid, is a prominent feature of Alzheimer’s Disease.
  • Levels of b-amyloid become elevated, and this protein undergoes a conformational transformation from a soluble helix-rich state to a state rich in beta sheets and prone to self-aggregaton.
mass spectrometry
Mass Spectrometry
  • Separates molecules based on MW
  • Peptides are vaporized
  • Applied charge propels the molecules down a bent tube
  • Molecules interact with magnetic field in tube
  • Where the molecules hit the side of the tube, which is the detector, gives their mass
mass spectrometry1
Mass Spectrometry
  • Since all A.A. except Leu and Isoleu have different masses, all AA present can be determined
  • Post translational modifications can also be determined with this method
  • The methods of vaporization vary and recent advances have allowed for larger peptides to be used.
  • Book discusses “Time of Flight” MS.
make sure you read
Make sure you read!!
  • Make sure you read Ch. 6. Remember, you are responsible for material not covered in lecture.
  • Example:
  • Fibrous Proteins: Structural materials of Cells and tissue. Be able to compare and contrast Karatins, Fibron, collagen, and elastin.