An introduction to Proteins, Protein Folding and the Lattice Model

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(An introduction to)Proteins, Protein Folding
and the Lattice Model

• Casey Lengacher
• University of Kentucky, CSURS Group

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Introduction

• What are proteins?
• Linear polymers of amino acids linked by peptide
  bonds in a specific sequence
• Large molecules, consisting of some permutation
  of different amino acids
• Acids are linked together via covalent chemical
  bonds called peptide bonds
• These links are grouped together to form
  polypeptide chains

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Classifications

• Type of polypeptide structure
• Monomeric versus Oligomeric
• Chemical composition
• Simple versus Conjugate
• Biological function
• Catalyst enzymes for chemical reactions
• Structure keratin, collagen, elastin
• Transport hemoglobin
• Many others

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Structures

• Function is closely related to shape
• Aspects of structure divided into levels
• Primary the sequence of the amino acid
• Secondary linear helix or zigzag pattern
• Tertiary three-dimensional folded structure
• Quaternary multiple chains behaving as one
• The precise structure, or functional structure,
  is called the native state or lowest energy
  state
• Modified structures result in a denatured protein

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Synthesis
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Problems

• Modern science has established, working models
  for primary structures but still struggles with
  predicting tertiary structures.
• Developing a strong model for tertiary structure
  predictions is important because the tertiary
  structure most reflects a proteins function.

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Historical Perspective

• 1838 Jons J. Berzelius
• The existence of biological materials different
  from lipids, polysaccharides, and nucleic acid
• 1953 Crick and Watson
• The structure of deoxyribonucleic acid
• 1954 Christian Anfinsen
• Proves theoretically the primary sequence
  contains enough information to determine tertiary
  structure

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Turning Point

• Anfinsens work was very significant.
• While proof was valid, techniques were limited
• Lacked an algorithm, forced most computations
• Spent a great deal of time after 1954 developing
  rules for protein folding related to
  thermodynamics and molecular interaction
• Assistance would come 15 years later in the form
  of a paradox

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Levinthals Paradox

• 1968-1969 Cyrus Levinthal
• Suggested that folding mechanism was not a random
  sampling
• The operation must be fast
• To explain this, there must exist non-native
  permutations sitting in local deep wells of low
  energy, but not the global low energy
• Algorithms based on relaxation techniques may be
  able to verify these results

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Model Evolution

• Several models begin to develop
• Framework Model elements form independently in
  the secondary structure, then collide to form the
  tertiary structure
• Nucleation Model spontaneous formation of bits
  of the secondary structure, which then act as
  nuclei from which further structure builds
• Hydrophobic Collapse Model protein collapses to
  hide its hydrophobic side chains, and then
  rearranges to its final tertiary structure

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Models for Models

• Lattices can be used to reduce complexity
• Several different kinds, but most work on the
  principle of reducing an near infinite set of
  outcomes to a more realistic number.
• Typical lattice model construction
• A single self-avoiding string (SAP) representing
  the polypeptide chain
• Beads placed at the nodes can represent the
  constraining entities
• Intuitively, the best SAP would be the one that
  represents the lowest energy level, but is it
  really that simple?

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Lattices

• So what is a lattice anyways?
• Grid based model, that can be multi-dimensional,
  typically consisting of nodes connected by
  relationships in a structured pattern
• The nodes and connections can be objects and
  relationships that have some real world
  application
• Understanding the application is vital to picking
  a node arrangement that will work

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HP Lattice Model

• An example of the lattice model applied to the
  Hydrophobic Collapse Model
• One method to evaluating the optimal SAP is by
  analysis if the Unconnected Neighboring Nodes
  (UNN)
• In a simple two-type HP model, 4 UNN combinations
  are possible HP, HH, PP, and PH.
• Each combination is given a weight, typically
  based on the hydrophobic count.
• The SAP with the lowest score is indicated as the
  most likely candidate.

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HP Lattice Model
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Problems

• The lattice model approach does have problems.
• The biggest problem is that in a square model,
  pairing becomes an issue
• Pairing in a square model eliminates interaction
  between acids that are not in an even odd
  pairing
• To overcome this, some have suggested using a
  triangular lattice model

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Algorithm Analysis

• Read in a source for the shapes
• Apply the sequence to each shape, determining the
  energy level
• Output can be in graphical form or tabular
• Algorithm can become more complex if less is
  known about the input sequences

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Future Ideas

• Is there room for additional improvements?
• Could the lattice model be made to model the real
  world more accurately?
• So far, most research involves variations in node
  arrangement.
• Could relationships along the SAP be weighted?
• Could a weighted approach eliminate the pairing
  problem in the square conformation?

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Thanks

• Dr. Jaromczyk
• CSURS Group
• University of Kentucky