NMRQ: Quality Assessment and Validation for Protein Structures Generated by NMR Spectroscopy

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NMRQ Quality Assessment and Validation for
Protein Structures Generated by NMR Spectroscopy
Gary Van Domselaar gvd_at_redpoll.pharmacy.ualb
erta.ca May 06, 2005
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Introduction

• Protein structure determination is important for
• Protein functional characterization
• Rational drug design
• Biological understanding
• Protein structures must be reliable and accurate
  to be useful.
• Protein structures can be determined by X-ray
  crystallography and by NMR spectroscopy

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Introduction

• Protein structure generation by either method is
  prone to experimental and interpretation error.
• Protein structure analysis programs are available
  to assess protein structure quality
• WHATCHECK
• PROCHECK PROCHECK-NMR
• PROVE
• SQUID
• VADAR
• MOLPROBITY
• Coming Soon NMRQ!

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Introduction

• Protein Structure Validation Packages
• Verify the structure file syntax
• Check the consistency of the structure against a
  library of high-quality structures and identify
  outliers
• Detect gross errors in the model
• Check for local stereochemical abnormalities
• Produce a score to describe the quality of the
  structure

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WHAT CHECK

• Stereochemical Analysis
• Postscript/Text/HTML
• Z Scores
• Crude Graphics
• Does not perform ensemble analysis

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PROCHECK-NMR

• Sterochemical Analysis
• Restraint Analysis via AQUA
• Ensemble Analysis
• Postscript
• Good Graphics
• Times Cited 6390

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NMRQ

• Sterochemical Analysis
• Restraint Analysis
• Ensemble Analysis
• Chemical Shift Analysis
• Superposition and RMSD
• HTML Reports

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NMRQ
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NMRQ
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NMRQ Superposition
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NMRQ Superposition
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NMRQ Superposition
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Torsion Angle Analysis
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Torsion Angle Analysis
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Torsion Angle Analysis
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Torsion Angle Analysis
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Torsion Angle Analysis
Favorable
Allowed
Generously Allowed
Disallowed
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Torsion Angle Analysis
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Torsion Angle Analysis
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Torsion Angle Analysis
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Chi Angle Analysis
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Relation Between ? and ???
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SCWRL

• The SCWRL rotamer library is a backbone dependant
  rotamer library
• aa phi psi
  prob. chi1 chi2 chi3 chi4
  sd1 sd2 sd3 sd4
• ARG -180 -180 6 1 1 1 1
  0.002977 55.4 79.7 62.4 82.3
  19.8 16.1 15.0 11.9
• ARG -180 -180 6 1 1 1 2
  0.006091 59.2 85.4 68.2 -166.5
  23.2 16.6 15.4 25.6
• ARG -180 -60 0 1 3 3 1
  0.000078 63.6 -77.9 -77.1 102.9
  23.8 19.7 21.6 14.2

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NMRQ Chi Angle Analysis

• Adds the probability values for all chi angle
  distributions within /- 20 degrees, for a given
  phi, psi.
• Sequence Chi1 Probability
  Secondary Structure
• Y-1 -64.90 0.00000
  C
• K-2 -73.10 0.43090
  C
• C-3 166.20 0.00000
  C
• G-4 0.00 0.00000
  C
• L-5 -54.90 0.60453
  C

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Aside Parsing the SCWRL Library

• -rw-rw-r-- 1 gvd gvd 4.0K Dec 13
  1657 RotamerLibrary.index.dir
• -rw-rw-r-- 1 gvd gvd 2.0M Dec 13
  1657 RotamerLibrary.index.pag
• -rw-r--r-- 1 gvd gvd 48M Dec 13
  1128 RotamerLibrary.txt
• unless (self-gt_ROTAMER_LIBRARY"res phi
  psi")
• tie (rotLib, 'SDBM_File', dbPath,
  O_RDONLY,0666) throw ErrorSimple("CreateRotam
  erLibrary Could not create the DB !")
• my key "res phi psi"
• my val rotLibkey
• get the info from file.
• my (start,offset) split(/\,/,val)
• seek(LIBRARY, start,0)
• my buffer
• read(LIBRARY,buffer,offset)
• ...
• push _at_self-gt_ROTAMER_LIBRARY"res phi
  psi", \row

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(No Transcript)
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Chi Angle Analysis
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Chi Angle Analysis
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Volume and Area
Loose Packing Dense Packing Protein
Proteins are Densely Packed
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Volume and Area
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Volume and Area
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Volume and Area
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Volume and Area
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(No Transcript)
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Volume and Area
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Chemical Shift Analysis
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Chemical Shift Analysis
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Chemical Shift Analysis
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Chemical Shift Analysis
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Chemical Shift Analysis
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Other Statistics
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Other Statistics
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Other Statistics
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Other Statistics
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Other Statistics
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Summary Reports
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Summary Reports
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Summary Reports
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Restraint Analysis
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Restraint Analysis

• Coming Soon...
• PROCHECK-NMR AQUA
• Distance restraints plot
• Restraint differences plot
• Numbers of distance restraints
• Actual distance - restraint summary
• Violation frequency summary
• Restraint statistics
• Residue-by-residue restraint violations
• Model-by-model violations

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NMRQ TODO List

• Chi angle plots, and cumulative plots
• Restraint analysis
• Model and ensemble scoring statistics
• Syntax Validation

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NMRQ Limitations

• NO Chi1-Chi2 Torsion Angle Distribution
• PDB parsing not robust, no validation
• Hydrogen bond analysis available, not
  implemented.
• Insert your comments here.

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Acknowledgements

• Dr. Paul Stothard
• Trent Bjorndahl
• Steve Neal
• Prof. David Wishart