Re: AMBER: NMR vs. X-ray structures

From: Marc Baaden <>
Date: Tue, 12 Jun 2007 07:51:21 +0200

Dear Sally,
we have just published a comparison of NMR vs X-ray starting structures
on the MD of membrane proteins [1]. Although it was difficult to draw
any firm conclusions you might find it interesting.
There was also a previous study comparing the influence of the quality
of the starting structures for MD simulations showing that short MD
simulations can discriminate 'bad' structures from good ones [2].
Marc Baaden

Outer membrane proteins: comparing X-ray and NMR structures by MD simulations in lipid bilayers
K Cox, PJ Bond, A Grottesi, M Baaden, MSP Sansom; European Biophysics Journal, 2007
Membrane protein structure quality in molecular dynamics simulation
RJ Law, C Capener, M Baaden, PJ Bond, J Campbell, G Patargias, Y Arinaminpathy, MSP Sansom
J Mol Graphics & Modeling, 2005, 24, 157 said:
>> I am wondering whether anyone knows of a systematic study of the
>> behavior of NMR versus X-ray protein structures during MD
>> simulations.
>> I noticed in the amber reflector archives that NMR structures are
>> known to have a tendency to show less stability than X-ray structures
>> (per Yong Duan, October 2003). I am looking for any publications
>> that may demonstrate this trend and that may offer some explanation
>> for it.
>> Otherwise, I would be grateful for any explanation that you all
>> might offer.
>> I have naively carried out a series of MD simulations starting with
>> an NMR protein structure (wild-type and in silico point mutants),
>> using a 20 ps equilibration to 300 K. During subsequent 5 ns
>> production runs, I am seeing RMSD's averaging 4 to 6 Angstroms. I
>> later carried out identical simulations on a homologous protein, for
>> which both NMR and X-ray structures exist. While the NMR structure
>> again gave an RMSD peaking at 6 Angstroms over 5 ns, the X-ray
>> structure's RMSD reached only 1.5 Angstroms over the same timescale.
>> Do you think that a longer, more elaborate equilibration would lessen
>> this discrepancy? Can I trust any of the NMR-based data I have
>> gathered so far, or is the RMSD out of a believable range?
>> Thank you for your help.
>> Sally

Abstract 1:
The structures of three bacterial outer membrane proteins (OmpA, OmpX and PagP) have been determined by both X-ray diffraction and NMR. We have used multiple (7 ? 15 ns) MD simulations to compare the conformational dynamics resulting from the X-ray versus the NMR structures, each protein being simulated in a lipid (DMPC) bilayer. Conformational drift was assessed via calculation of the root mean square deviation as a function of time. On this basis the ‘quality’ of the starting structure seems mainly to influence the simulation stability of the transmembrane ?-barrel domain. Root mean square fluctuations were used to compare simulation mobility as a function of residue number. The resultant residue mobility profiles were qualitatively similar for the corresponding X-ray and NMR structure-based simulations. However, all three proteins were generally more mobile in the NMR-based than in the X-ray simulations. Principal components analysis was used to identify the dominant motion!
s within each simulation. The first two eigenvectors (which account for >50% of the protein motion) reveal that such motions are concentrated in the extracellular loops and, in the case of PagP, in the N-terminal ?-helix. Residue profiles of the magnitude of motions corresponding to the first two eigenvectors are similar for the corresponding X-ray and NMR simulations, but the directions of these motions correlate poorly reflecting incomplete sampling on a ?10 ns timescale.

Abstract 2:
Our goal was to assess the relationship between membrane protein quality, output from protein quality checkers and output from molecular dynamics (MD) simulations. Membrane transport proteins are essential for a wid range of cellular processes. Structural features of integral membrane proteins are still under-explored due to experimental limitations in structure determination. Computational techniques can be used to exploit biochemica and medium resolution structural data, as well as sequence homology to known structures, and enable us to explore the structure?function relationships in several transmembrane proteins. The quality of the models produce is vitally important to obtain reliable predictions. An examination of the relationship between model stability in molecular dynamics (MD) simulations derived from RMSD (root mean squared deviation) and structure qualit assessment from various protein quality checkers was undertaken. The results were compared to membrane prote!
in structures, solved at various resolution, by either X-ray or electron diffraction techniques. The checkin programs could predict the potential success of MD in making functional conclusions. MD stability was shown to be a good indicator for the quality of structures. The quality was also shown to be dependent on the resolution a which the structures were determined
 Dr. Marc Baaden  - Institut de Biologie Physico-Chimique, Paris      -
 FAX: +33 15841 5026  -  Tel: +33 15841 5176  ou  +33 609 843217
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Received on Wed Jun 13 2007 - 06:07:28 PDT
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