Download Lesson20ProteinStructureSearches

Doug Raiford
Lesson 18
5/23/2017
Protein Structure Searches
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Given a protein conformation can we find
other structurally similar proteins?
Might have a database of structures (like the
PDB)
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Protein Structure Searches
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Can do a simple RMSD to compare the two
conformations
Know precisely which aa’s compare to which
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Protein Structure Searches
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Must map aa’s from one to aa’s in
the other
How might you do this?
Sequence similarity
MSA’s
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Protein Structure Searches
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3D PSSM
 Sequence alignment
integrated with 3D alignment
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Stored in profile (position
specific similarity profile)
 Gens 1D profiles first (MSAs)
 Then uses a structural
alignment program (SAP) to
augment profiles with
structural similarity
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Protein Structure Searches
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Aligning secondary structures
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Protein Structure Searches
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What do you think of
when you hear that
you will need to align
two things?
Dynamic
programming
α α α T β β β
α
α
β
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β
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Protein Structure Searches
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Three components
 AA similarity (substitution matrix)
 Local structure
▪ E.g. both aa’s members of alpha helix
 Solvent exposure
Are the
associated AA’s
similar, sequence
wise (i.e. both
glycines)?
Are they both in a
similar local structure?
Are they both buried or
both exposed to solvent?
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SAP (structure alignment) allows a profile to
be influenced by secondary structure
Useful to 3D PSSM in that
threading decisions (which
aa’s match to a profile)
Homology based protein
conformation enhanced
by making better decisions on where to insert
gaps/varying length loops
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Protein Structure Searches
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PFAM
 Have Markov Models for protein families
 Sequences that match models have high
probability of matching conformation
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Even though not comparing structures
(query to target)
 are matching a sequence to its most
probable structure
HMMR
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Protein Structure Searches
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Can’t really align
How else might it work?
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Protein Structure Searches
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How might two distance matrices
look?
 All pair wise distances from each aa to all
other aa’s
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If identical proteins the matrices
would be almost identical
Low
distance
region if
hair pin
(antiparallel)
Low distance
region in
matrix if
parallel
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Protein Structure Searches
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Find optimum set of similar
sub-structures
 Even if in different 1D locations
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Find amino acid equivalence
Once have equivalence can
easily compare structure
similarity
 E.g. with RMSD
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Protein Structure Searches
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Break matrix into a bunch
of overlapping submatrices
Do an all pair wise
comparison
Sub-matrices are merged
that naturally extend
Must find pairings of submatrices that yield best
overall score
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6 7
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Monte Carlo approach
 Randomly generate pairings
 Calculate overall similarity
Multiple solutions in parallel
Slowly improve each by
randomly altering pairings
(like a random search)
 Have some probability of
keeping a solution that is
worse than previous
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Can determine similarity
How?
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Protein Structure Searches
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Must perturb XYZ
(translation), pitch,
and yaw (rotation) of
one of the proteins
minimizing RMSD
Like linear regression
Can’t do until know
which aa’s are
associated
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Protein Structure Searches
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Some numeric methods
start by fixing between 2
and 4 amino acids
Some short cuts
 Center of gravity is the
average of all vectors
 Translate
▪ ave(p1) – ave(p2)
 Singular value decomposition
to rotate (Like Eivenvectors)
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Requires double dynamic
programming
 If nxm matrix then n times m
α α α T
α α α T
α α α T
α
α α α T
α
α αα
α
β αα
β
β
β
different matrices generated
pinning return path to each aa pair
 Used to generate a position
specific scoring which is then used
in aa similarity scoring
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Reduces the constraint that two
particular aa’s are equivalent
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Protein Structure Searches
α α α T
α
α
β
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