Restrained molecular dynamics calculations

Fig. 2.47 The (P)-2.5-helical structure of N.N -linked oligoureas as determined by NMR meaurements in pyridine-c/5. (A) Stereo-view along the helix axis of a low energy conformer of nonamer 178 generated by restrained molecular dynamics calculations. (Adapted from [274]). The helix is characterized by (i) a rigid +)-SYnclinal arrangement around the C(a)-...

If all nuclei are assigned and the spectral parameters for the conformational analysis are extracted, a conformation is calculated - usually by distance geometry (DG) or restrained molecular dynamics calculations (rMD). A test for the quality of the conformation, obtained using the experimental restraints, is its stability in a free MD run, i.e. an MD without experimental restraints. In this case, explicit solvents have to be used in the MD calculation. An indication of more than one conformation in fast equilibrium can be found if only parts of the final structure are in agreement with experimental data [3]. Relaxation data and heteronuclear NOEs can also be used to elucidate internal dynamics, but this is beyond the scope of this article. 

Figure 6 Model of d(CGCTpS -TpS -AAGCG) derived from NOESY-distance restrained, molecular dynamics calculations.

Figure 19.6 Arrangement of the three consecutive base pairs G2-C71, G3-U70, and G4-C69 a) in the starting structure (as created with the BIOPOLYMER module of INSIGHT II) obtained from a regular Watson-Crick A-RNA duplex with a G3-C70 base pair after subsequent replacement of the C70 residue by a uridine. No further adjustment of the U70 base position has been made and hence no correct hydrogen bonding pattern is found b) in the final (average) structure derived from relaxation matrix analysis of the 300 ms NOESY spectrum using the IRMA procedure [45] and restrained molecular dynamics calculation. Note that G3 and U70 now are forming a regular base pair. The bases G3 and U70 are indicated by thick lines.

The overall aim is usually to determine the complete 3D structure of a nucleic acid and this is achieved in the same fashion as for protein structures. Thus, the NMR spectra are interpreted in terms of qualitative or semi-quantitative distance information which is then used as a set of constraints for a theoretical calculation of the structure generally based on distance geometry or restrained molecular dynamics calculations. One of the main problems with this approach, unlike for proteins, is the lack of long-range distance constraints for double-helix structures. 

You can include geometric restraints—for interatomic distances, bond angles, and torsion angles—in any molecular dynamics calculation or geometry optim i/.ation. Here are some applications of restrain ts ... 

The default restraints are appropriate for molecular dynamics calculations where larger force constants would create undesirable high frequency motions but much larger force constants may be desired for restrained geometry optimization. 

MI Sutcliffe, CM Dobson, RE Oswald. Solution structure of neuronal bungarotoxm determined by two-dimensional NMR spectroscopy Calculation of tertiary structure using systematic homologous model building, dynamical simulated annealing, and restrained molecular dynamics. Biochemistry 31 2962-2970, 1992. 

Fig. 6.8 Correlation of experimental and theoretical residual dipolar couplings calculated using the structural data obtained from restrained molecular dynamics with NOEs, dihedral angle and RDCs-...

The most definitive proof of p-sheet structure requires the determination of the three-dimensional solution structure of the peptide. For the calculation of such structures one requires the accurate determination of coupling constants by DQF-COSY experiments which give backbone dihedral restraints and through-space connectivities (ROESY or NOESY experiments) which give rise to distance restraints. A combination of these restraints allows the calculation of the three-dimensional structure of the peptide using restrained molecular dynamics simulations. Utilizing this methodology, the three-dimensional structures of a number of cyclic peptides have been solved.[411... 

Recently, Lindorff-Larsen el al.uo included the order parameter (S 2) in the target function, and refined an ubiquitin X-ray structure by restrained molecular dynamics (Section 6.4) to obtain an NMR structure ensemble (Section 6.5) from the trajectories. They simulated the values of RDCs (Section 9.1) and side chain scalar coupling from the calculated ensemble to confirm that the method can determine the protein three-dimensional structure and dynamic structure simultaneously. The simulated values were in good agreement with the corresponding measurement data. The simulation accuracy was improved from the preliminary calculated structure without the order parameters. The approach is typically important, because they tried to link the ensemble with a dynamic structure directly. 

Homology modeling using simulated annealing of restrained molecular dynamics and conformational search calculations with CONGEN application in predicting the three-dimensional structure of murine homeodomain Msx-1. 

The structure of splendipherin has been determined using restrained molecular dynamics and simulated annealing calculations. The resultant structure is currently being employed in molecular modelling calculations using the CHARMM package. The structure and mechanism of movement of splendipherin will be published together when this work is complete. 

As mentioned above, the cross peak intensities from NOESY spectra taken at long mixing times caimot be related in a simple and direct way to distances between two protons due to spin diffusion effects that mask the actual proton distances. A possibiUty to extract such information is provided by relaxation matrix analysis that accounts for all dipolar interactions of a given proton and hence takes spin diffusion effects explicitly into consideration. Several computational procedures have been developed which iteratively back-calculate an experimental NOESY spectrum, starting from a certain molecular model that is altered in many cycles of the iteration process to fit best the experimental NOESY data. In each cycle, the calculated structures are refined by restrained molecular dynamics and free energy minimization [42,43]. 

Figure 19.7 Model of the tRNA acceptor arm structure as determined on the basis of the 300 ms NOESY spectrum using the IRMA procedure [45] and restrained molecular dynamics. Three structures resulting from different calculations are superimposed. The continuation of the helix geometry into the single-stranded terminus is clearly visible. The black sphere marks the most probable location of the bound manganese ion in the vicinity of G3-U70 base pair.

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