Comparison of Aqueous Molecular Dynamics with NMR Relaxation and Residual Dipolar Couplings Favors Internal Motion in a Mannose Oligosaccharide
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- 作者：Andrew Almond ; Jakob Bunkenborg ; Thomas Franch ; Charlotte H. Gotfredsen ; and Jens Ø ; . Duus
- 刊名：Journal of the American Chemical Society
- 出版年：2001
- 出版时间：May 23, 2001
- 年：2001
- 卷：123
- 期：20
- 页码：4792 - 4802
- 全文大小：209K
- 年卷期：v.123,no.20(May 23, 2001)
- ISSN：1520-5126
文摘
An investigation has been performed to assess how aqueous dynamical simulations of flexiblemolecules can be compared against NMR data. The methodology compares state-of-the-art NMR data (residualdipolar coupling, NOESY, and 13C relaxation) to molecular dynamics simulations in water over severalnanoseconds. In contrast to many previous applications of residual dipolar coupling in structure investigationsof biomolecules, the approach described here uses molecular dynamics simulations to provide a dynamicrepresentation of the molecule. A mannose pentasaccharide, 
-D-Manp-(1
3)--D-Manp-(13)--D-Manp-(13)--D-Manp-(12)-D-Manp, was chosen as the model compound for this study. The presence of -linkedmannan is common to many glycopeptides, and therefore an understanding of the structure and the dynamicsof this molecule is of both chemical and biological importance. This paper sets out to address the followingquestions. (1) Are the single structures which have been used to interpret residual dipolar couplings a usefulrepresentation of this molecule? (2) If dynamic flexibility is included in a representation of the molecule, canrelaxation and residual dipolar coupling data then be simultaneously satisfied? (3) Do aqueous moleculardynamics simulations provide a reasonable representation of the dynamics present in the molecule and itsinteraction with water? In summary, two aqueous molecular dynamics simulations, each of 20 ns, were computed.They were started from two distant conformations and both converged to one flexible ensemble. The measuredresidual dipolar couplings were in agreement with predictions made by averaging the whole ensemble andfrom a specific single structure selected from the ensemble. However, the inclusion of internal motion wasnecessary to rationalize the relaxation data. Therefore, it is proposed that although residual dipolar couplingscan be interpreted as a single-structure, this may not be a correct interpretation of molecular conformation inlight of other experimental data. Second, the methodology described here shows that the ensembles fromaqueous molecular dynamics can be effectively tested against experimental data sets. In the simulation, significantconformational motion was observed at each of the linkages, and no evidence for intramolecular hydrogenbonds at either (12) or (13) linkages was found. This is in contrast to simulations of other linkages,such as 
beta2.gif" BORDER=0 ALIGN="middle">(14), which are often predicted to maintain intramolecular hydrogen bonds and are coincidentallypredicted to have less conformational freedom in solution.
-D-Manp-(13)--D-Manp-(13)--D-Manp-(13)--D-Manp-(12)-D-Manp, was chosen as the model compound for this study. The presence of -linkedmannan is common to many glycopeptides, and therefore an understanding of the structure and the dynamicsof this molecule is of both chemical and biological importance. This paper sets out to address the followingquestions. (1) Are the single structures which have been used to interpret residual dipolar couplings a usefulrepresentation of this molecule? (2) If dynamic flexibility is included in a representation of the molecule, canrelaxation and residual dipolar coupling data then be simultaneously satisfied? (3) Do aqueous moleculardynamics simulations provide a reasonable representation of the dynamics present in the molecule and itsinteraction with water? In summary, two aqueous molecular dynamics simulations, each of 20 ns, were computed.They were started from two distant conformations and both converged to one flexible ensemble. The measuredresidual dipolar couplings were in agreement with predictions made by averaging the whole ensemble andfrom a specific single structure selected from the ensemble. However, the inclusion of internal motion wasnecessary to rationalize the relaxation data. Therefore, it is proposed that although residual dipolar couplingscan be interpreted as a single-structure, this may not be a correct interpretation of molecular conformation inlight of other experimental data. Second, the methodology described here shows that the ensembles fromaqueous molecular dynamics can be effectively tested against experimental data sets. In the simulation, significantconformational motion was observed at each of the linkages, and no evidence for intramolecular hydrogenbonds at either (12) or (13) linkages was found. This is in contrast to simulations of other linkages,such as beta2.gif" BORDER=0 ALIGN="middle">(14), which are often predicted to maintain intramolecular hydrogen bonds and are coincidentallypredicted to have less conformational freedom in solution.