Conformational dynamics of proline residues in antamanide. J Coupling analysis of strongly coupled spin systems based on E.COSY spectra

Mádi, Z. L.; Griesinger, C.; Ernst, R. R.

doi:10.1021/ja00164a010

Cited by 73 publications

(46 citation statements)

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“…As the accuracy of this type of measurements is critically dependent on the signal-to-noise ratio, we have repeated 13 C spin-lattice relaxation time measurements of GPGG using a higher-field NMR spectrometer (14.1 T, 600 MHz 1 H frequency) and a cryoprobe (Tables SII and SIII, Supporting Information). For the analysis of the T 1 values and deriving correlation times, we have used the approach developed by Ernst et al .,82,83 which is different to that used by Mikhailov et al 68. The following equations were used to derive the correlation times for the overall (τ c ) and the intramolecular ring interconversion (τ e ) processes from the measured T 1 relaxation times82–84: where Δθ is the jump angle of the C—H bond on conformational transition, γ H and γ C are gyromagnetic ratios of 1 H and 13 C, ħ is Planck's constant divided by 2π, r CH = 1.09 Å is the C—H bond length, Δσ is the chemical anisotropy of the 13 C nucleus considered (see Experimental), N is the number of H atoms attached to the C atom.…”

Section: Resultsmentioning

confidence: 99%

Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics

et al. 2013

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We propose a new approach for force field optimizations which aims at reproducing dynamics characteristics using biomolecular MD simulations, in addition to improved prediction of motionally averaged structural properties available from experiment. As the source of experimental data for dynamics fittings, we use 13C NMR spin-lattice relaxation times T1 of backbone and sidechain carbons, which allow to determine correlation times of both overall molecular and intramolecular motions. For structural fittings, we use motionally averaged experimental values of NMR J couplings. The proline residue and its derivative 4-hydroxyproline with relatively simple cyclic structure and sidechain dynamics were chosen for the assessment of the new approach in this work. Initially, grid search and simplexed MD simulations identified large number of parameter sets which fit equally well experimental J couplings. Using the Arrhenius-type relationship between the force constant and the correlation time, the available MD data for a series of parameter sets were analyzed to predict the value of the force constant that best reproduces experimental timescale of the sidechain dynamics. Verification of the new force-field (termed as AMBER99SB-ILDNP) against NMR J couplings and correlation times showed consistent and significant improvements compared to the original force field in reproducing both structural and dynamics properties. The results suggest that matching experimental timescales of motions together with motionally averaged characteristics is the valid approach for force field parameter optimization. Such a comprehensive approach is not restricted to cyclic residues and can be extended to other amino acid residues, as well as to the backbone. Proteins 2014; 82:195–215. © 2013 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics

et al. 2013

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“…5-8 Hz. Recent NMR studies of proline-ring conformations in a cyclic peptide [33] and in proteins [34] have shown that both 'J(a,P) coupling constants in the range 5-8 Hz are characteristic of proline-ring flips. The 'J(aJ3) values observed for the cis-4-aminoproline moiety in 5 (Tubte 4 ) indicate a preferred ring pucker similar to conformer I in Fig.…”

Section: 2mentioning

confidence: 99%

Protein‐Loop Mimetics: A Diketopiperazine‐Based Template to Stabilize Loop Conformations in Cyclic Peptides Containing the NPNA and RGD Motifs

Bisang

Weber

1996

Helvetica Chimica Acta

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We explore here an approach to mimic the structures and biological functions of protein loops in small synthetic molecules, by grafting the loop of interest onto an organic template comprising a bicyclic diketopiperazine, prepared by the formal coupling of (2S,4S)-4-aminoproline (Pro(NH,)) and aspartic acid (Asp). The Fmoc-protected template 4 is used to prepare cycle(-Ala'-Asn2-Pro3-Asn4-Ala5-Ala6-Temp-) (5) and cyclo(-Ala'-Arg2-Gly3-Asp4-Temp-) (6) (where Temp = template derived from 4), containing the Asn-Pro-Asn-Ala (NPNA) and Arg-Gly-Asp (RGD) motifs. The conformational properties of these molecules are studied in aqueous solution by NMR and simulated-annealing methods. The NPNA motif, an immunodominant epitope on the circumsporozoite surface protein of the malaria parasite Plrrsmodium fakiparum, is shown to adopt a stable type-I 8-turn in 5.The template in 5 adopts a preferred conformation with Pro(NH,) x1 N -35O and the Asp moiety x I N 70". A different template conformation is inferred for 6, with Pro(NH,)X I N 0", but the ARGD loop appears by NMR to undergo rapid conformational averaging. Solid-phase binding assays reveal that 6 displays modest antagonist activity towards both the integrin a,& and GI& receptors.

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“…A system of a polypeptide in solution will have a variety of relaxation times, which are associated with different types of motions. For example, ring puckering of proline residues in the decapeptide antamanide has a T % 30 ps, whereas the slowest relaxation times involving peptide plane flips are tsystcm z 1 ps [52]. For biomolecular systems a computer simulation only covers relaxation times up to 0.1 -1 ns.…”

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confidence: 99%

On the interpretation of biochemical data by molecular dynamics computer simulation

Gunsteren

Mark

1992

European Journal of Biochemistry

135

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The application of computer simulation to molecular systems of biochemical interest is reviewed.It is shown that computer simulation is a tool complementary to experimental methods, which can be used to access atomic details inaccessible to experimental probes. Examples are given in which computer simulation augments the experimental information by providing an atomic picture of high resolution with respect to space, energy or time.The usefulness of a computer simulation largely depends on its quality. The most important factors that limit the accuracy of sirnulatcd results are discussed. The accuracy of different simulation studies can differ by orders of magnitude. The accuracy will depend on the type of biomolecular system and process studied. It will also depend on the choice of force field, the simulation set-up and the protocol that is used. A list of quality-determining factors is given, which may be useful when interpreting simulation studies appearing in the literature.The continuous advance of experimental techniques is steadily increasing our knowledge of biochemical systems and processes. A detailed picture of many biomolecular processes is emerging due to the possibility of measuring atomic properties of biological macromolecules, such as proteins. X-ray diffraction has provided a three-dimensional picture of biomolecular assemblies of ever increasing size, ranging from small proteins to a complete macromolecular reaction centre. Other experimental techniques, like nuclear magnetic resonance (NMR) and other spectroscopic methods, yield less complete information at the atomic level. However, the development of multi-dimensional NMR has made it possible to determine the spatial structure of small proteins, albeit at low resolution. The advantage of spectroscopic measuring techniques over X-ray diffraction methods is that the former can be used to obtain information on the dynamics of specific atoms or groups of atoms in the biomolecule, while the latter only yield an indication of the mobility of atoms, not of the time scale of their motion. The other major step forward is the advent of the possibility to change the amino acid composition of a protein at will. Instead of studying the proteins with which nature has provided us, we may now make specific mutations and study their effect on protein properties.Yet, the developing experimental techniques have specific limitations. Site-specific mutagenesis only allows the substitution of naturally occurring amino acids. Detailed structural, energetic and dynamic information at the atomic level on the

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Conformational dynamics of proline residues in antamanide. J Coupling analysis of strongly coupled spin systems based on E.COSY spectra

Cited by 73 publications

References 0 publications

Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics

Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics

Protein‐Loop Mimetics: A Diketopiperazine‐Based Template to Stabilize Loop Conformations in Cyclic Peptides Containing the NPNA and RGD Motifs

On the interpretation of biochemical data by molecular dynamics computer simulation

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