Comparing pharmacophore models derived from crystallography and NMR ensembles

Ghanakota, Phani; Carlson, Heather
November 2017
Journal of Computer-Aided Molecular Design;Nov2017, Vol. 31 Issue 11, p979
Academic Journal
NMR and X-ray crystallography are the two most widely used methods for determining protein structures. Our previous study examining NMR versus X-Ray sources of protein conformations showed improved performance with NMR structures when used in our Multiple Protein Structures (MPS) method for receptor-based pharmacophores (Damm, Carlson, J Am Chem Soc 129:8225-8235, 2007). However, that work was based on a single test case, HIV-1 protease, because of the rich data available for that system. New data for more systems are available now, which calls for further examination of the effect of different sources of protein conformations. The MPS technique was applied to Growth factor receptor bound protein 2 (Grb2), Src SH2 homology domain (Src-SH2), FK506-binding protein 1A (FKBP12), and Peroxisome proliferator-activated receptor-γ (PPAR-γ). Pharmacophore models from both crystal and NMR ensembles were able to discriminate between high-affinity, low-affinity, and decoy molecules. As we found in our original study, NMR models showed optimal performance when all elements were used. The crystal models had more pharmacophore elements compared to their NMR counterparts. The crystal-based models exhibited optimum performance only when pharmacophore elements were dropped. This supports our assertion that the higher flexibility in NMR ensembles helps focus the models on the most essential interactions with the protein. Our studies suggest that the 'extra' pharmacophore elements seen at the periphery in X-ray models arise as a result of decreased protein flexibility and make very little contribution to model performance.


Related Articles

  • NMR Assignment and Secondary Structure of the Coxsackievirus and Adenovirus Receptor Domain 2. Jiang, Shaokai; Caffrey, Michael // Protein & Peptide Letters;Aug2005, Vol. 12 Issue 6, p537 

    The Coxsackievirus and Adenovirus receptor (CAR) mediates entry of coxsackievirus and adenovirus. CAR possesses an extracellular region that is comprised of 2 Ig domains termed CAR-D1 and CAR-D2. The 1H, 13C and 15N resonances of CAR-D2 have been assigned and the secondary structure has been...

  • Molecular structures of methyl 4-[(1,3-dioxo-1,3-dihydro-2 H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazol-5-carboxylate and methyl 4-[(1,3-dioxo-1,3-dihydro-2 H-isoindol-2-yl)methyl]-1-methyl-1 H-pyrazol-3-carboxylate. Sakhautdinov, I.; Batyrshin, I.; Fatykhov, A.; Yumabaeva, V.; Suponitskii, K.; Antipin, M.; Yunusov, M. // Journal of Structural Chemistry;Mar2013, Vol. 54 Issue 2, p383 

    The structure of methyl 4-[(1,3-dioxo-1,3-dihydro-2 H-isoindol-2-yl)methyl]-1-methyl-1 H-pyrazol-5-carboxylate is determined by X-ray crystallography and further used to elucidate the structure of methyl 4-[(1,3-dioxo-1,3-dihydro-2 H-isoindol-2-yl)methyl]-1-methyl-1 H-pyrazol-3-carboxylate,...

  • A method for probing the mutational landscape of amyloid structure. O'Donnell, Charles W.; Waldispühl, Jérôme; Lis, Mieszko; Halfmann, Randal; Devadas, Srinivas; Lindquist, Susan; Berger, Bonnie // Bioinformatics;Jul2011, Vol. 27 Issue 13, pi34 

    Motivation: Proteins of all kinds can self-assemble into highly ordered β-sheet aggregates known as amyloid fibrils, important both biologically and clinically. However, the specific molecular structure of a fibril can vary dramatically depending on sequence and environmental conditions, and...

  • Bayesian Weighting of Statistical Potentials in NMR Structure Calculation. Mechelke, Martin; Habeck, Michael // PLoS ONE;Jun2014, Vol. 9 Issue 6, p1 

    The use of statistical potentials in NMR structure calculation improves the accuracy of the final structure but also raises issues of double counting and possible bias. Because statistical potentials are averaged over a large set of structures, they may not reflect the preferences of a...

  • Nuclear magnetic resonance molecular photography. Khitrin, Anatoly K.; Ermakov, Vladimir L.; Fung, B. M. // Journal of Chemical Physics;10/15/2002, Vol. 117 Issue 15, p6903 

    A procedure is described for storing a two-dimensional (2D) pattern consisting of 32×32 = 1024 bits in a spin state of a molecular system and then retrieving the stored information as a stack of nuclear magnetic resonance spectra. The system used is a nematic liquid crystal, the protons of...

  • ISOLATION OF A NEW DITERPENE FROM SIDERITIS CONGESTA. �ktemer, A.; Lo&gcaron;o&gcaron;lu, E. // Communications Series B Chemistry & Chemical Engineering;2003, Vol. 49 Issue 1, p1 

    Linearol (3�, 7a-Dihydroxy-18-acetoxykaur-16-ene) (1) as major compound and Siderol-18palmitate (C36H60O4) (2) have been isolated from Sideritis congesta. The structures of these compounds have been established by spectroscopic methods as �H-NMR, Mass spectroscopy (molecular peak) and...

  • In-depth understanding of Ï€-electron systems: New vistas in fullerene endohedrals. Yamada, Michio; Tsuchiya, Takahiro; Akasaka, Takeshi; Nagase, Shigeru // Pure & Applied Chemistry;Apr2010, Vol. 82 Issue 4, p757 

    The synthesis and characterization of various endohedral metallofullerenes and their derivatives are described. The encapsulated metal atoms' positions and movements were determined using NMR study, X-ray crystallographic analysis, and theoretical calculations. The results of electrochemical...

  • 1.2 Ã… X-ray Structure of the Renal Potassium Channel K1.3 T1 Domain. Kremer, Werner; Weyand, Michael; Winklmeier, Andreas; Schreier, Christina; Kalbitzer, Hans // Protein Journal;Oct2013, Vol. 32 Issue 7, p533 

    Here we present the structure of the T1 domain derived from the voltage-dependent potassium channel K1.3 of Homo sapiens sapiens at 1.2 Ã… resolution crystallized under near-physiological conditions. The crystals were grown without precipitant in 150 mM KP, pH 6.25. The crystals show I4...

  • NMR Is Ready, so Bring on the Macromolecules. DePalma, Angelo // Genomics & Proteomics;Jan/Feb2005, Vol. 5 Issue 1, p26 

    Discusses nuclear magnetic resonance (NMR) spectroscopy as a tool for protein elucidation. Comparison with X-ray crystallography in protein and RNA structure studies; NMR's capabilities that enable the investigation of dynamic properties of molecules, particularly protein-small molecule...

  • Structural basis for engagement by complement factor H of C3b on a self surface. Morgan, Hugh P.; Schmidt, Christoph Q.; Guariento, Mara; Blaum, Bärbel S.; Gillespie, Dominic; Herbert, Andrew P.; Kavanagh, David; Mertens, Haydyn D. T.; Svergun, Dmitri I.; Johansson, Conny M.; Uhrín, Dušan; Barlow, Paul N.; Hannan, Jonathan P. // Nature Structural & Molecular Biology;Apr2011, Vol. 18 Issue 4, p463 

    Complement factor H (FH) attenuates C3b molecules tethered by their thioester domains to self surfaces and thereby protects host tissues. Factor H is a cofactor for initial C3b proteolysis that ultimately yields a surface-attached fragment (C3d) corresponding to the thioester domain. We used NMR...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics