MOLDYN: a generalized program for the evaluation of molecular dynamics models using nuclear magnetic resonance spin-relaxation data

Craik, David J.; Kumar, Anil; Levy, George C.

doi:10.1021/ci00037a006

Cited by 55 publications

(26 citation statements)

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“…(9) For 15 N nuclei in small proteins, the main mechanisms of relaxation influenced by molecular motion are dipole–dipole interactions with directly bonded protons and chemical shift anisotropy. (22) The observed relaxation data T 1 (=1/ R 1 ), T 2 (=1/ R 2 ), and NOE are related by equations (1), (2), and (3) to the spectral density function, J (ω).…”

Section: Methodsmentioning

confidence: 99%

“…NMR relaxation measurements contain information about the motions of molecules because the nuclear spin relaxation is mediated by fluctuating local magnetic fields, caused by overall and internal molecular motion. (9) In the initial structural study on RTD-1, the observation of some broadened peaks led to the suggestion that the molecule is flexible in solution, undergoing a “butterfly”-type motion (Figure 1c). (7) However, later structures of RTD-1 and other θ-defensins suggested a more rigid backbone(6) based on minimal disorder in the ensemble of NMR structures.…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Molecular Flexibility of θ-Defensins by NMR Relaxation Analysis

Conibear¹,

Wang²,

et al. 2014

J. Phys. Chem. B

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θ-Defensins are mammalian cyclic peptides that have antimicrobial activity and show potential as stable scaffolds for peptide-based drug design. The cyclic cystine ladder structural motif of θ-defensins has been characterized using NMR spectroscopy and is important for their structure and stability. However, the effect of the pronounced elongated topology of θ-defensins on their molecular motion is not yet understood. Studies of molecular motion by NMR relaxation measurements have been facilitated by the recent development of a semirecombinant method for producing cyclic peptides that allows for isotopic labeling. Here we have undertaken a multifield 15N NMR relaxation analysis of the anti-HIV θ-defensin, HTD-2, and interpreted the experimental data using various models of overall and internal molecular motion. We found that it was necessary to apply a model that includes internal motion to account for the variations in the experimental T1 and NOE data at different backbone amide sites in the peptide. Although an isotropic model with internal motion was the simplest model that provided a satisfactory fit with the experimental data, we cannot exclude the possibility that overall motion is anisotropic, especially considering the strikingly elongated topology of θ-defensins. The presence of flexible side chains, self-association, interactions with solvent, and internal motions are all potential contributors to the observed relaxation data. Internal motion consistent with the constraints imposed by the cyclic cystine ladder was observed in that the order parameters, S2, show that residues in the turns are more flexible than those in the β-sheet. This study provides insights into the dynamics of θ-defensins and information that might be useful in their application as scaffolds in drug design.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insights into the Molecular Flexibility of θ-Defensins by NMR Relaxation Analysis

Conibear¹,

Wang²,

et al. 2014

J. Phys. Chem. B

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“…Details of the program and calculation procedure by employing various models have been given elsewhere. 10,23 …”

Section: Methodsmentioning

confidence: 99%

¹³C Nuclear Magnetic Relaxation Study of Segmental Dynamics of Hyaluronan in Aqueous Solutions

et al. 2005

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(13)C spin-lattice relaxation times (T(1)) and nuclear Overhauser enhancements (NOE) were measured as a function of temperature and magnetic field strength for the hetero-polysaccharide hyaluronan in water solutions. The relaxation data of the endocyclic ring carbons were successfully interpreted in terms of chain segmental motions by using the bimodal time-correlation function of Dejean de la Batie, Laupretre and Monnerie. On the basis of the calculated correlation times for segmental motion and amplitudes of librational motions of the C-H vectors at the various carbon sites of the HA repeating unit, we concluded that intramolecular hydrogen bonding of the secondary structure of HA plays a major role in the conformational flexibility of this carbohydrate molecule. The internal rotation of the free hydroxymethyl groups about the exocyclic C-5-C-6 bonds superimposed on segmental motion has been described as a diffusion process of restricted amplitude. The rate and amplitude of the internal rotation indicate that the hydroxymethyl groups are not involved in intramolecular hydrogen bonding. Finally, the motional parameters describing the local dynamics of the HA chain were correlated with the secondary structure of HA in aqueous solutions.

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“…The measured and calculated relaxation parameters using the DLM and MFA models are summarized in Table 2. The relaxation data were analyzed by using the MOLDYN program [17] modified by us to include the spectral density functions used in the present study. The parameters of a given model were optimized until the sum of the squares of deviations of the difference between theoretical and experimental relaxation data reached a minimum.…”

Section: Comparison Of the Models Through Simulation Of Nmr Datamentioning

confidence: 99%

Critical Comparison of Two Models Describing Segmental Dynamics of Polymer Chains in Dilute Solutions

Kanetakis

Dais²

2001

Macromol. Theory Simul.

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MOLDYN: a generalized program for the evaluation of molecular dynamics models using nuclear magnetic resonance spin-relaxation data

Cited by 55 publications

References 2 publications

Insights into the Molecular Flexibility of θ-Defensins by NMR Relaxation Analysis

Insights into the Molecular Flexibility of θ-Defensins by NMR Relaxation Analysis

¹³C Nuclear Magnetic Relaxation Study of Segmental Dynamics of Hyaluronan in Aqueous Solutions

Critical Comparison of Two Models Describing Segmental Dynamics of Polymer Chains in Dilute Solutions

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MOLDYN: a generalized program for the evaluation of molecular dynamics models using nuclear magnetic resonance spin-relaxation data

Cited by 55 publications

References 2 publications

Insights into the Molecular Flexibility of θ-Defensins by NMR Relaxation Analysis

Insights into the Molecular Flexibility of θ-Defensins by NMR Relaxation Analysis

13C Nuclear Magnetic Relaxation Study of Segmental Dynamics of Hyaluronan in Aqueous Solutions

Critical Comparison of Two Models Describing Segmental Dynamics of Polymer Chains in Dilute Solutions

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¹³C Nuclear Magnetic Relaxation Study of Segmental Dynamics of Hyaluronan in Aqueous Solutions