Are time-averaged restraints necessary for nuclear magnetic resonance refinement?

Pearlman, David A.; Kollman, Peter A.

doi:10.1016/0022-2836(91)90024-z

Cited by 141 publications

(98 citation statements)

References 51 publications

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“…When restrained molecular dynamics refinement is performed on a bound ligand in the absence of the receptor, the danger exists that regions of the ligand that are poorly restrained by NOES will adopt conformations that are influenced by the force field of the free ligand. Refinement methods that beter represent the limitations of the NOE restraints, such as MD using time-averaged restraints [32,33], are a useful means to avoid overestimating the precision of the final structures.…”

Section: Discussionmentioning

confidence: 99%

“…5). MD simulations run in the presence of time-averaged restraints [32,33] indicate that the NOE restraints are insufficient to precisely define the orientation of this ring, instead allowing it to pivot through a range of acg!es. Hence, the precise orieztetion of this ring in the final MD-refined NMR structures is apparently dictated partly by the MD force field.…”

Section: Conformation Of Bound Fk506mentioning

confidence: 99%

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Solution structure of FK506 bound to FKBP‐12

1992

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The complex of the immunosuppressant FK506 bound to FKBP-I? has been studied in solution using 'H and inverse-detected "C NMR methods. The resonances of bound, "C-1abellcd FK506 were assigned and a set of 66 inttaligand NOE distance restraints were used to calculate the structure of the bound ligdnd by distance geometry and restrained molecular dynamics methods. The structure of bound FKS06 in solution closely resembles that seen in the X-ray structure [ 171, except for the ally1 region. The differences reflect the inlluencc ol' intermolecular crystal contacts and have implications for interpretation of the internction of the FKSOBlFKBP complex with its putalive biological receptor.

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Section: Discussionmentioning

confidence: 99%

Section: Conformation Of Bound Fk506mentioning

confidence: 99%

Solution structure of FK506 bound to FKBP‐12

1992

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“…The SA model of the AMBER program was used to speed up the conformational search. The time-averaged restraint method (63,66,67) was used to include interproton-distance (a total of 40) and dihedral-angle (a total of 16, pertaining to angles for Ala residues, and angles for O residues, and , , and angles for X residues) restraints determined from the ROE intensities and coupling constants, respectively. Because of overlapping of the peaks of the H ␣ and H ␤ protons, it was not possible to determine the dihedral angles and angles alanines and for ornithines.…”

Section: Methodsmentioning

confidence: 99%

Polyproline II conformation is one of many local conformational states and is not an overall conformation of unfolded peptides and proteins

Makowska

Rodziewicz‐Motowidło

Bagiñska

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

161

200

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The alanine-based peptide Ac-XX(A)7OO-NH2, referred to as XAO (where X, A, and O denote diaminobutyric acid, alanine, and ornithine, respectively), has recently been proposed to possess a well defined polyproline II (P II) conformation at low temperatures. Based on the results of extensive NMR and CD investigations combined with theoretical calculations, reported here, we present evidence that, on the contrary, this peptide does not have any significant amount of organized P II structure but exists in an ensemble of conformations with a distorted bend in the N-and C-terminal regions. The conformational ensemble was obtained by molecular dynamics͞simulated annealing calculations using the AMBER suite of programs with time-averaged distance and dihedralangle restraints obtained from rotating-frame nuclear Overhauser effect (ROE) volumes and vicinal coupling constants 3 JHN⌯␣, respectively. The computed ensemble-averaged radius of gyration R g (7.4 ؎ 1.0) Å is in excellent agreement with that measured by small-angle x-ray scattering (SAXS) whereas, if the XAO peptide were in the P II conformation, Rg would be 11.6 Å. Depending on the pH, peptide concentration, and temperature, the CD spectra of XAO do or do not possess the maximum with positive ellipticity in the 217-nm region, which is characteristic of the P II structure, reflecting a shifting conformational equilibrium rather than an all-or-none transition. The ''P II conformation'' should, therefore, be considered as one of the accessible conformational states of individual amino acid residues in peptides and proteins rather than as a structure of most of the chain in the early stage of folding.CD spectroscopy ͉ molecular dynamics ͉ NMR spectroscopy ͉ polyproline type II structure ͉ unfolded state of proteins T he structures of proteins under denaturing conditions have received considerable attention from experimentalists (1-19) and theoreticians (20-32). The dominating model has been the statistical coil (erroneously called a random coil) developed by Flory (20) and corroborated by Tanford (1). However, recent work (9, 10) suggests that the end-to-end distances in denatured proteins need not conform to statistical-coil polymer-like distributions.Recently, Kallenbach and coworkers (11) carried out CD and NMR studies of an alanine-based peptide Ac-XX(A) 7 OO-NH 2 (where X, A, and O denote diaminobutyric acid, alanine, and ornithine, respectively), hereafter referred to as XAO, and proposed that XAO has a dominant polyproline II (P II ) structure at 2°C and that the content of the ␤-strand is increased by Ϸ10% at 55°C relative to that at 2°C. Based on the temperature dependence of the CD spectra of XAO, they stated that there is a transition from the low-temperature P II conformation to a ␤-structure; in other words, the P II conformation at low temperatures is the state of most residues of the whole peptide rather than the state that pertains to a subset of individual amino acid residues. Subsequently, the XAO peptide has been considered as a model of P II stru...

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“…The HN-C A H spin-spin accounting of conformationally averaged NMR experimental data. A time-averaged model was used in distance-based refinecoupling constants for Arg9, His10, Ser12 and Cys13 residues are close to the values typical for random coil peptides (Table ment [12,13] or in refinement directly against the NOE crosspeak volumes [15]. An alternative approach treats experimental 1) and do not allow us to restrain the corresponding torsion angles.…”

Section: Resultsmentioning

confidence: 99%

Two distinct structures of α‐conotoxin GI in aqueous solution

Maslennikov

Sobol

Gladky

et al. 1998

European Journal of Biochemistry

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The detailed analysis of conformational space of A-conotoxin GI in aqueous solution has been performed on the basis of two-dimensional NMR spectroscopy data using multiconformational approach. As the result, two topologically distinct interconvertible sets of GI conformations (populations of 78% and 22%) have been found. A common feature of the two sets is the Asn4-Cys7 β-turn. The Gly8 to Tyr11 region has a structure of right-handed helical turn in the major set and two sequential bends in the minor one. N-terminus and C-terminus also have different orientations, anti-parallel in the major conformational set and parallel in the minor one. An average pairwise rmsd for backbone heavy atoms is 0.56 Å in the major set, 0.23 Å in the minor, and 1.85 Å between the structures of the two sets. The X-ray structure of GI [Guddat, L. W., Martin, J. A., Shan, L., Edmundson, A. B. & Gray, W. R. (1996) Biochemistry 35, 11 329Ϫ11 335] has the same folding pattern as the major NMR set, the average backbone rmsd between the two structures being 0.77 Å .Keywords : conotoxin ; nicotinic acetylcholine receptor; NMR; conformational analysis.The venom of marine snails of the Conus genus contains structure, dynamics, and their relationship with the biological function of peptides. However, in practice high-resolution X-ray oligopeptide neurotoxins which are sophisticated tools for studying a wide range of receptors and ion channels : A-conotoxins structures of small flexible peptides are often biased by crystal packing forces and may differ from a biologically active conforblock nicotinic acetylcholine receptors (nAChR), µ-conotoxins and ω-conotoxins act on voltage-gated sodium and calcium mation. In turn, NMR spectroscopy faces technical difficulties when dealing with flexible molecules. Quite often it is stated channels, respectively, while the targets of the contatokins are the N-methyl-D-aspartate receptors (see review [1]). The most that a number of different conformations in fast exchange are present in solution, among which one can expect a biologically numerous family is that of A-conotoxins consisting of over 10 members whose primary structure has been established and bio-active conformation. Several techniques were proposed for analysis of NMR data on flexible molecules [11Ϫ18], but the logical activity analysed. The efficiency of the interaction between nAChR and A-conotoxins depends on the species and sub-problem is still far from being solved. Here we introduce a new approach for the analysis of NMR data of flexible peptides and type of the nAChR. Most of A-conotoxins block the neuromuscular nAChR. However, several recently discovered A-conotox-show that A-conotoxin GI in aqueous solution is represented by two topologically distinct sets of interconvertible conformations. ins act on neuronal nAChR [2]. Besides the above-mentioned species-selectivities and subtype-selectivities, recent data describe the affinity and binding selectivity to the Torpedo membranes or to AChR in the mouse cell line for the naturally occur-MA...

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Are time-averaged restraints necessary for nuclear magnetic resonance refinement?

Cited by 141 publications

References 51 publications

Solution structure of FK506 bound to FKBP‐12

Solution structure of FK506 bound to FKBP‐12

Polyproline II conformation is one of many local conformational states and is not an overall conformation of unfolded peptides and proteins

Two distinct structures of α‐conotoxin GI in aqueous solution

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