3-Dimensional Structure of Proteins 4 levels of protein structure:

The three dimensional structure of proteins

Protein: string of amino acids

One particular string:

• Strong fibrous structure found in hair, wool

Another:

• Oxygen transporter in blood

Another:

• Molecular motor

Why are:

‰ pieces of DNA with different sequencesso similar

‰ pieces of protein with different sequencesso different????

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DNA:

• Little chemical difference between subunits

• Subunits interact with each other in limited ways• Basically same structure

structure is sequence independentNot entirely true…

Protein:• Significant chemical differences between subunits

• Subunits interact with each other in many ways

• Enormous (infinite??) variety of structures…Structure is defined by the sequence

Function is defined by the structure

‘ Key biochemical concept: Structure and function are intimately related

Major focus of modern biochemistry:• how protein sequence defines protein structure

‘ can structure be predicted from sequence????• how a particular structure accomplishes

a particular function

Common units of secondary structure:

• Alpha helix • Beta sheet


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3-Dimensional Structure of Proteins

Elements of protein structure

Conformation:

• Spatial arrangement of atoms in a protein

Possible conformations:Any structural states that can be achieved

without breaking covalent bonds

-> rotation

Consider covalent backbone of protein --If free rotation were possible…

But:

Each protein has a particular chemical or structural function‘ suggests each protein has a characteristic 3-d structure

Of the huge number of theoretically possible conformations,a few predominate under biological conditions:

• Thermodynamically most stable (usually…)• Folded, functional (“active”) conformations• “native” conformation

Why do proteins fold?

“simple thermodynamics…”

‰ If Gfolded < Gunfolded, the protein will fold

∆G=∆H-T∆S

„ Why is Gfolded < Gunfolded ?

• Isn’t much less∆G separating folded and unfolded ~20 to 65 kJ/mol

• Folded proteins have lots of hydrogen bondsbut folding makes R groups lose H bonds with water…

• Unfolded protein has highly structured water shellFolded protein has much smaller water shell

‘ Protein folding driven primarily byincrease in entropy resulting from loss of orderedwater shell around unfolded protein

• ∆S term drives protein to fold• Sum of specific weak interactions (∆H term)

- hydrogen bonding- ionic interactions- van der Waals interactions

define the specific folded state

The peptide bond:• rigid

• planar

Partial double bond character of C-N bond:

‰ The peptide C-N bond is NOT free to rotate‰ Rotation IS permitted around N-Cα and Cα-C bonds

Backbone o f apolypeptide chai :n• serie s of rigid planes• common rotation point a t Cα



Rotations at Cα:N-Cα bo :nd φ

Cα -C bond: ψ



‰ Most conceivable φ,ψ angles are not sterica lly possible

Ramachandra n plot for L -Ala:



Common units of secondary structure:

• Alpha helix • Beta sheet


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4 levels of protein structure:

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Alpha HelixCommon structure: ~25% of all amino acid residues!

(hair…)Optimal use of internal hydrogen bonding: 1st -4th

Alpha-helicesare generallyright handed

Interactions between R groups can either• stabilize or

• destabilize

alpha helices

‘ Important interactions are betweenamino acids 3 to 4 residues apart

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Amino acids rare in alpha helices:

Proline: too constrined

Glycine: no R group, too flexible

Different faces of alpha helices can have differentcharacterisitics:

Helical Wheel:


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Interactions of R groups with dipole:Stabilizes or destabilizes the alpha helix

Alpha helices have an intrinsic dipole:



3 constraints affect stability of alpha helix:1)interactions between adjacent R groups

• steric• electrostatic

2) Occurrence of Pro and Gly3) interactions between AAs at end of helix and

intrinsic dipole

Example: α-keratinHai ,r fingernails, horn,s hooves…

Simple repeating righ -t hande d alpha-helix• Parallel coile -d coil

twist ed like a rope• Coile -d coils assembl e int oprotofilaments, protofibrils

‘ quaternary structure

Characterisitcs of α−keratin:

• Strong• Flexible• Stretchy

Amino acids at surfaceswhere helices touch:

‘ Hydrophobic, intermeshing R groups





Coiled-coils:Common in structural proteins

Large number of cytoskeletal proteins

myosin

Characteristics of alpha helices:



• Strong• Flexible

• Stretchy

Not limited to coiled-coils!!Common structural units

Why does hair sometimes curl?• Hair has cysteines which can form disulfide bonds

• Disulfide bonds between filaments introduce twists

How does a “permanent” cause hair curling?

1) Reducing agent used to treat hair-- breaks native disulfi de bonds

2) Hair is treatest with moist heat-- extends/unfolds the hair alpha helices, allowing

hair to be “bent” into the desired shape

3) oxidizing agent is added to form new disulfide bondsthat keep hair in newly bent shape



Disulfide bonds: more than curls!hardness of horn…





Beta Sheets (silk…)• Extended “zigzag” conformation

(repeat 6.5-7 angstrom)

• R groups protrude in opposite directions-alternating pattern

• Hydrogen bonds are between adjacent “strands”

• Adjacent strands can be- contiguous in primary sequence or

- from different polypeptides

• R groups protruding out of each “face” may haveparticular characterisitcs:

Faces water: hydrophilic

Faces membrane: hydrophobic

Faces another β shee :t small‘ create alternating pattern in

primary sequence

SilkNotealternatingGly/Alaresidues

• Doesn’t stretch: ß conformation already extended(3.5Å /residue)

• Flexible: sheets are held together by numerousweak interactions





Alpha helices are much more compact than β sheets

Relativ e lengt h o f a585 AA peptidein differen t conformations:









Proteins can have mostly alpha helix, beta sheet, or both

Other secondary structures also exist! (tomorrow…)

3-Dimensional Structure of Proteins 4 levels of protein structure:

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