Visualizing Protein Structures

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Visualizing Protein Structures

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Genetic information, stored in DNA, is conveyed
as proteins
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Genetic information, stored in DNA, is conveyed
as proteins
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The immediate product of translation is the
primary protein structure
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General Amino Acid Structure
H
COOH
H2N
Ca
R
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List of Amino Acids and Their Abbreviations
Nonpolar (hydrophobic)
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Polar (hydrophilic)
Electrically Charged (negative and hydrophilic)
Electrically Charged (positive and hydrophilic)
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General Amino Acid Structure
H
COOH
H2N
Ca
R
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Peptide Bond Formation
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Peptides have rotatable bonds of defined lengths

• Note- all proteins have polarity- N termini C
  termini

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The protein-folding problem.

• Proteins -- hundreds of thousands of different
  ones -- are the biochemical molecules that make
  up cells, organs and organisms. Proteins put
  themselves together, in a process termed
  "folding." How they do that is called "the
  protein-folding problem," and it may be the most
  important unanswered question in the life
  sciences.
• WHY??

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• The primary sequence dictates the secondary and
  tertiary structure of the protein

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Protein Structure
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Two questions

• Can you change the 3o (tertiary) sequence without
  changing the 1o (primary) sequence?
• Can you change the 1o (primary) sequence without
  changing the 3o (tertiary) sequence?

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What is known about protein folding?

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Secondary Structures are dominated by

• 1) a-helix
• 2) b-sheet

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• a-helical structure is a very regular structure
  (3.6 amino acids/turn)

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b-sheet anti-parallel
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b-sheet parallel
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Hydrogen Bonding And Secondary Structure
beta-sheet
alpha-helix
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Hydrogen Bonding

• One of the most important stabilizing forces in
  protein structure!
• Both ?-helix and ?-sheet are dependent on
  H-bonding.

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Protein Folding is progressive?

• 1 - first
• 2- second
• 3 - third

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Formation of tertiary structure

• The tertiary structure (or conformation) is the
  way alpha -helixes and beta -pleated sheets fold
  in respect to each other.
• Amino acids which are very distant in the primary
  structure might be close in the tertiary one
  because of the folding of the chain.

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Structure Stabilizing Interactions (Factors
governing 3 structure)

• Noncovalent
• Van der Waals forces (transient, weak electrical
  attraction of one atom for another)
• Hydrophobic (clustering of nonpolar groups)
• Hydrogen bonding
• Salt bridges
• Covalent
• Disulfide bonds

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Hydrophobic and Hydrophilic Interactions

• Hydrophilic amino acids are those whose
  sidechains offer hydrogen bonding partners to the
  surrounding water molecules.

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• Hydrophobic amino acids
• Tend to internalize in water.
• Tend to externalize in a membrane

• Hydrophilic amino acids
• Tend to externalize in water.
• Tend to internalize in a membrane

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Disulfide Bridge
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Disulfide Bridge Linking Distant Amino Acids
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Structure Stabilizing Interactions (Factors
governing 3 structure)

• Noncovalent
• Van der Waals forces (transient, weak electrical
  attraction of one atom for another)
• Hydrophobic (clustering of nonpolar groups)
• Hydrogen bonding
• Salt bridges
• Covalent
• Disulfide bonds

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• Protein G Structure Tutorial

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• The transformation happens quickly and
  spontaneously. It takes only a fraction of a
  second for a floppy chain of beads to fold into
  the shape it will keep for the rest of its
  working life.
• How does that happen? How do the linear -- and,
  in some sense, one-dimensional -- structures of
  proteins carry the information that tells them to
  take on permanent three-dimensional shapes? Is it
  possible to study a protein chain and predict the
  folded shape it will take?
• That is the protein-folding problem.

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DNA sequencing information ? predictions of the
primary amino acid sequence.

• Needed- Software that will convert the 1o
  sequence to its corresponding 3o sequence.
• Needed- Software that will describe a 1o
  sequence that will generate a particular 3o
  sequence.

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Structure classification

• Finding proteins that have similar chemical
  architectures.
• This involves developing a representation of how
  units of secondary structure come together to
  form domains.
• compact regions of structure within the large
  protein structure.

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• The Protein Data Bank

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The End
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• WHY IS PROTEIN FOLDING SO DIFFICULT TO
  UNDERSTAND?
• It's amazing that not only do proteins
  self-assemble -- fold -- but they do so amazingly
  quickly some as fast as a millionth of a second.
  While this time is very fast on a person's
  timescale, it's remarkably long for computers to
  simulate. In fact there is a 1000 X gap between
  the simulation timescales (nanoseconds) and the
  times at which the fastest proteins fold
  (microseconds).

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A Glimpse of the Holy Grail?

• The prediction of the native conformation of a
  protein of known amino acid sequence is one of
  the great open questions in molecular biology and
  one of the most demanding challenges in the new
  field of bioinformatics. Using fast programs and
  lots of supercomputer time, Duan and Kollman (1)
  report that they have successfully folded a
  reasonably sized (36-residue) protein fragment by
  molecular dynamics simulation into a structure
  that resembles the native state. At last it seems
  that the folding of a protein by detailed
  computer simulation is not as impossible as most
  workers in the field believe.

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Proteins from Scratch

• Not long ago, it seemed inconceivable that
  proteins could be designed from scratch. Because
  each protein sequence has an astronomical number
  of potential conformations, it appeared that only
  an experimentalist with the evolutionary life
  span of Mother Nature could design a sequence
  capable of folding into a single, well-defined
  three-dimensional structure. But now, on page 82
  of this issue, Dahiyat and Mayo (1) describe a
  new approach that makes de novo protein design as
  easy as running a computer program. Well almost.

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Progress in the protein-folding problem?

• When proteins fold, they dont try ever possible
  3D conformation. Protein folding is an orderly
  process (i.e. there are molecular shortcuts
  involved).

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Success in protein-folding?

• Given the primary sequence of a protein, the
  success rate in predicting the proper 3D
  structure of a protein shows strong correlation,
  to the of the protein that showed similarity to
  proteins of known structure.

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• The primary sequence dictates the secondary and
  tertiary structure of the protein