Protein Conformation Prediction (Part II)

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Protein Conformation Prediction (Part II)

• Doug Raiford
• Lesson 18

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Review two folding models

• Framework model
• Secondary structure first
• Assemble secondary structure segments
• Hydrophobic collapse
• Molten compact but denatured
• Formation of secondary structure after settles
  in
• van der Waals forces and hydrogen bonds require
  close proximity

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Two approaches

• De novo (or ab initio)
• From the beginning or from first principles
• Comparative/Homology Based
• Sequence similarity

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Homology based

• Find a similar protein of known structure
• Structure should be similar

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How

• Know the phi and psi angles of the similar
  protein
• Can apply those same angles
• Known as threading

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Threading issues

• What are chances that lengths will the same
• Where put longer portions
• Where put gaps

Once again, MSAs
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Popular homology based approach

• 3D PSSM (Threading Server)
• Remember?
• Position specific similarity matrix
• Profiles
• 3D PSSM performs MSAs but augments with
  additional 3D alignments
• Aligning known 3D conformations in three
  dimensions

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De Novo Approaches

• Molecular dynamics
• Summation of all forces exerted at all locations
  simultaneously
• Computationally intensive
• Do not fully understand such forces as
  hydro-phobic avoidance of solvent

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Middle ground

• Secondary structure prediction
• Accuracy mid to upper 70s
• Work the loops to fold secondary structures into
  energetically optimal conformation

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One approach

• See how often aas show up at specific positions
  in secondary structure
• Chou-Fasman
• Empirical parameters for ?, ?, and ? -turns
• P(?,aa)f(aa)/ave(?)
• P(?,aa)f(aa)/ave(?)
• P(?-turn,aa)f(aa)/ave(?-turn)

• Name P(a) P(b) P(turn)
• Alanine 142 83 66
• Arginine 98 93 95
• Aspartic Acid 101 54 146
• Valine 106 170 50

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Algorithm

• ID regions where 4 out of 6 (3 of 5 for ?)
  contiguous residues have P(a-helix) gt 100
• Extend the helix in both directions until a set
  of four contiguous residues that have an average
  P(a-helix) lt 100 is reached.

1 MAKYNEKKEK KRIAKERIDI LFSLAERVFP YSPELAKRYV
ELALLVQQKA HHHHH HHHHHHHHHH H
HHHHHHHH HHHHHHHHHH 51 KVKIPRKWKR RYCKKCHAFL
VPGINARVRL RQKRMPHIVV KCLECGHIMR T SSTTTT SB
TTT B BTTTEEEEE E SSS EEEE EETTTTEEEE 101
YPYIKEIKKR RKEKMEYGGL VPR EE
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For turns

• Chou and Fasman also determined turn frequencies
• Most hairpins are three in length
• When p(?-turn) f(j)f(j1)f(j2)f(j3) is
  greater than P(?) or P(?)

• Name P(a) P(b) P(turn) f(i)
  f(i1) f(i2) f(i3)
• Alanine 142 83 66 0.06
  0.076 0.035 0.058
• Arginine 98 93 95 0.070
  0.106 0.099 0.085
• Aspartic Acid 101 54 146 0.147
  0.110 0.179 0.081
• Valine 106 170 50 0.062
  0.048 0.028 0.053

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Patterns in usage

• Patterns can be used to augment these
  statistical approaches
• In some cases, one side of helices like water
• Every 4th aa hydrophilic
• Helps ID helix
• Helps ID that solvent exposed
• Other patterns coiled coils

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Sounds like

• Does this sound familiar?
• Probability of a sequence of occurrences?

Hairpin position 1
Hairpin position 2
Hairpin position 3
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HMMSTR

• Hidden Markov Model
• Hidden states helix, beta sheet, turn

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Motifs

• Proteins organized into
• Domains
• Domains composed of motifs
• PFAM
• Database of protein families
• Hidden Markov Models

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HMMR and PFAM
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CASP

• Critical Assessment of techniques for protein
  Structure Prediction
• Biannual conference contest
• Secret newly experimentally determined structures

CASP1 (1994) CASP2 (1996) CASP3 (1998)
CASP4 (2000) CASP5 (2002) CASP6 (2004)
CASP7 (2006) CASP8 (2008) CASP9 (2010)
CASP10(2012)
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CASP evaluation

• Root mean square (RMS) for angles
• No intermol contacts
• Secondary structure
• Surface
• Buried

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Approaches

• Have seen comparative homology based
• HMM based rely on multiple sequence alignments
  homology
• Now turn to De novo
• Split into two Ab initio and knowledge based

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ROSETTA (CASP3 Winner) De Novo Knowledge based

• Build a list of possible conformations (25) for
  each segment (length 9)
• Predicted secondary structure
• Database of structures
• Randomly draw from this list, apply ? and f, and
  score conformation
• Monte Carlo simulated annealing procedure

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ROSETTA (CASP3 Winner)

• Scoring global conformation
• hydrophobic burial
• Electrostatics
• Disulfide bonding
• Main chain hydrogen bonding
• Strand pairing
• Sheet formation
• Helix-strand interactions
• Excluded volume

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Letter Name Definition
H Alpha helix (4-12) Two or more consecutive bridge partners at i and i4.
B Isolated beta-bridge residue Must not have a neighbor that qualifies it for H, E, G, or I status. Bridge partner is identified in BP1 or BP2 column.
E Strand ("extended") Has at least one bridge partner and at least one neighbor bridged in parallel or antiparallel.
G 3-10 helix Two or more consecutive bridge partners at i and i3.
I pi helix Two or more consecutive bridge partners at i and i5.
T Turn Bridge partner at i3, i4, or i5, but no bridged neighbor that would qualify them for H, G, or I status.
S Bend Local curvature greater than 70 degrees, measured as the angle between alpha carbons at i-2, i, and i2.
blank None Meets none of the criteria above.