Protein Structure Searches

Doug RaifordLesson 18

04/21/23 1Protein Structure Searches

Given a protein conformation can we find other structurally similar proteins?

Might have a database of structures (like the PDB)


Can do a simple RMSD to compare the two conformations

Know precisely which aa’s compare to which


Must map aa’s from one to aa’s in the other

How might you do this?Sequence similarityMSA’s


3D PSSM Sequence alignment

integrated with 3D alignment

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


Aligning secondary structures


What do you think of when you hear that you will need to align two things?

Dynamic programming

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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?

SAP (structure alignment) allows a profile to be influenced by secondary structure

Useful to 3D PSSM in thatthreading decisions (whichaa’s match to a profile)

Homology based protein conformation enhancedby making better decisions on where to insert gaps/varying length loops


PFAM Have Markov Models for protein

families Sequences that match models have

high probability of matching conformation

Even though not comparing structures (query to target) are matching a sequence to its most

probable structure


HMMRHMMR

Can’t really alignHow else might it work?


How might two distance matrices look? All pair wise distances from each

aa to all other aa’s If identical proteins the matrices

would be almost identical

Low distance region in matrix if parallel

Low distance region if hair pin (anti-parallel)04/21/23 12Protein Structure Searches

Find optimum set of similar sub-structures Even if in different 1D

locationsFind amino acid

equivalenceOnce have equivalence can

easily compare structure similarity E.g. with RMSD


Break matrix into a bunch of overlapping sub-matrices

Do an all pair wise comparison

Sub-matrices are merged that naturally extend

Must find pairings of sub-matrices that yield best overall score


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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?


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


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)


Requires double dynamic programming

If nxm matrix then n times m 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

Reduces the constraint that two particular aa’s are equivalent


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Protein Structure Searches

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