Lab Meeting 06/05/20051 NMRQ: Quality Assessment and Validation for Protein Structures Generated by...

Lab Meeting 06/05/2005 1

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

Gary Van Domselaar

[email protected]

May 06, 2005


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


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!


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


WHAT CHECK

• Stereochemical Analysis

• Postscript/Text/HTML• “Z” Scores• Crude Graphics• Does not perform

“ensemble analysis”


PROCHECK-NMR

• Sterochemical Analysis

• Restraint Analysis via AQUA

• Ensemble Analysis• Postscript• Good Graphics• Times Cited: 6390


NMRQ

• Sterochemical Analysis

• Restraint Analysis• Ensemble Analysis• Chemical Shift

Analysis• Superposition and

RMSD• HTML Reports


NMRQ


NMRQ


NMRQ: Superposition


NMRQ: Superposition


NMRQ: Superposition


Torsion Angle Analysis









Favorable

Allowed

Generously Allowed

Disallowed








Chi Angle Analysis


Relation Between and


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


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


Aside: Parsing the SCWRL Library

-rw-rw-r-- 1 gvd gvd 4.0K Dec 13 16:57 RotamerLibrary.index.dir

-rw-rw-r-- 1 gvd gvd 2.0M Dec 13 16:57 RotamerLibrary.index.pag

-rw-r--r-- 1 gvd gvd 48M Dec 13 11:28 RotamerLibrary.txt

unless ($self->{_ROTAMER_LIBRARY}{"$res $phi $psi"}) {

tie (%rotLib, 'SDBM_File', $dbPath, O_RDONLY,0666) || throw Error::Simple("CreateRotamerLibrary: Could not create the DB: $!");

my $key = "$res $phi $psi";

my $val = $rotLib{$key};

# get the info from file.

my ($start,$offset) = split(/\,/,$val);

seek(LIBRARY, $start,0);

my $buffer;

read(LIBRARY,$buffer,$offset);

...

push @{$self->{_ROTAMER_LIBRARY}{"$res $phi $psi"}}, \%row;

}


Chi-Angle Dispersion Correlates With Accessible Surface AreaFractional ASA


Chi Angle Analysis


Chi Angle Analysis


Volume and Area

Loose Packing Dense Packing Protein

Proteins are Densely Packed


Volume and Area


Volume and Area


Volume and Area


Volume and Area


Volume and Area

Solvent ProbeAccessible Surface

Van der Waals Surface

Reentrant Surface


Volume and Area


Chemical Shift Analysis










Other Statistics


Other Statistics


Other Statistics


Other Statistics


Other Statistics


Summary Reports


Summary Reports


Summary Reports


Restraint Analysis


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


NMRQ TODO List

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


NMRQ Limitations

• NO Chi1-Chi2 Torsion Angle Distribution• PDB parsing not robust, no validation• Hydrogen bond analysis available, not

implemented.• Insert your comments here.


Acknowledgements

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

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