Structural Alignment via Delaunay Tetrahedralization

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Structural Alignment via Delaunay
Tetrahedralization

• Charlie Carter and Jeffrey Roach
• Department of Biochemistry and Biophysics
• UNC Chapel Hill
• 22 August 2005 - NC AT

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Overview

• Problems associated with structural superposition
  and comparison
• Protein modularity and plasticity frustrate
  comparison by rigid bodies.
• Rigid body fitting is slow, especially in
  all-by-all contexts.
• Rigid body metrics (RMSD) may lead to
  inconsistent phylogenies.
• Mapping the Delaunay tetrahedralization to a
  string addresses all three problems.
• Delaunay and related (AD) tessellations capture
  both local and long-range contact information.
• TETRADA strings retain recoverable 3D structural
  information.
• APPLICATIONS
• Superposition
• Detecting internal symmetries
• Clustering multiple structural alignments
  phylogenies
• Clustering aligned MD snapshots functionality
  and mechanism of conformation changes
• Quantitative assessment of phylogenetic
  hypotheses

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Plasticity, modularity, and structural alignment

• Multiple rigid body transformations are necessary
  to identify the increased similarity between A
  and C, relative to that between B and C.
• Scoring relative homologies consistently is very
  problematic in such cases.

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Tetrahedral Decomposition Analysis strings
capture short, long range contacts
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Blocking and similarity scoring
Blocking Each edge sequence is broken into
blocks of contiguous integers

• 1A 2B 3A 4B 13C 87C 88B 89C 90B
• 1A 2B 3A 4B 13C 87C 88B 89C 90B
• 1A 2B 3A 4B
• 13C
• 87C 88B 89C 90B

1A 2B 77C 78C 79C 301C 302C 1A 2B 77C 78C
79C 301C 302C 1A 2B 77C 78C 79C 301C
302C
Scoring Each matching pair is given a score 2
if edge lengths match 1 if edge
lengths differ
Total edge sequence similarity 4 2 3 9
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TETRADA edge strings afford flexible
superposition via sequence alignment
C
C
N
N
TrpRS, GlnRS, MetRS, LeuRS HIGH sequences and a1
helices
Edge-length similarity (color) is highest at
N-terminus
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TETRADA matches ProSUP and Dali-lite
ProSup
Tetrada
Dali-lite
Histone 2A on Histone 3
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TETRADA strings retain recoverable 3D structural
information.

• TetraDA strings are analogous to data derived
  from a NMR structure determination using Nuclear
  Overhauser effects.
• gt Reformat edge strings consistent with input,
  together with sequence information, to CNS (a
  structure-determining package) and test recovery.
• Edge string information from Tetrada strings is
  sufficient for robust structure recovery.

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Recovery of Milky Ribbon-worm Mini-hemoglobin
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Structural recovery from TETRADA strings is
robust up to 900 residues
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Tetrada strings faithfully capture internal
symmetry, gene duplication.
Ferredoxin (52 residues)
Cytidine deaminase (294 residues)
Carbamoyl PO4-Synthetase (1037 residues)
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Clustering based on Tetrada similarity scores
captures distant relationships.
Dali-lite
Tetrada
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(No Transcript)
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Flexibile alignment allows Tetrada to captures
distant phylogenies
Cysteinyl-tRNA synthetase on Glutaminyl-tRNA
synthetase
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While also capturing subtle differences involved
in conformation changes.
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Large-dimensional clustering reveals microstates
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Molecular Dynamics reveals how ligands modulate
conformational energy profiles
State (analog)
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Residue-by-residue SNAPP profile scores show that
packing de- and re-stabilization is localized
Domain Hinge Repacking
lt Stabilizing D(SNAPP) Destabilizing gt
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Dot-plot comparison of Pre, Post TS TrpRS
structures
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Class I and II active sites are unrelated
Class II active sites
Class I active sites
but deeply interdependent
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The Rodin-Ohno Hypothesis complementary,
sense/antisense homology
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Ribas-Schimmel Pairwise structural
complementarity of aaRS
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Ribas-Schimmel hypothesis is supported at the 5
confidence level
Levels not connected by same letter are
significantly different
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Class I II Tertiary scaffolds can be coded as
SASORFs!!Carter Duax, Molecular Cell, (2002)
10705-708
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SerRS, HSP70 structural homology?Tetrada scoring
gt comprehensive similarity
Roach, et al., 2005, PROTEINS SFB, 6066-81
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Brought to you by the UNCrystallographers

• Jeffrey Roach-UNC
• Li Li-UNC
• Vita Weinreb-UNC
• Yen Pham
• Aram Kim-UNC

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Recovery of Green Alga Cytochrome C6