Mspin, RDC’s and efficient use of freely rotating groups

In the last ten years, Residual Dipolar Couplings (RDC) have come to occupy a very important place in the structure determination of proteins, nucleic acids and carbohydrates in liquid state. Although RDCs were originally discovered and theoretically explained for small molecules in liquid crystal solvents by A. Saupe in 1968 (Angew. Chem. Int. Ed. Engl. 1968, 7, 97) the spectra were too complex for a practical use in structure determination. The discovering of weak orienting media in water led to an explosion in the application of RDCs for biomolecule structure determination. However, those aligning media used for biomolecules were not applicable to most of the small molecules. Fortunately, recent research results considerably extended the applications of RDCs to small molecules as new alignment media for organic solvents, either liquid crystal type as poly-?-benzyl-L-glutamate (PBLG), or mechanically stretched cross-linked polymer gels such as poly(methyl methacrylate) gel (PMMA) or polydimethylsiloxane (PDMS) are available. If you are interested in RDCs you should certainly check the very didactic introduction in the theory by Kramer et al. Applications and practical considerations are nicely reviewed in the recent reviews by Cristina Thiele ( See this and this) and Burkhard Luy ( see this).

The use of RDCs in small molecule structural determination is typically based on the determination of the alignment tensor, a 3x3 matrix, which contains the information about the probability of the molecule pointing in a particular direction of the space. This matrix can be determined by least squares fitting to the experimental RDCs.
However, there exists a further potential problem on the application of RDC to the structure determination of small molecules: the lack of enough independent RDCs, i.e, those coming from non parallel vectors, since in most cases only 1DCH RDCs are available from F1 ( see this) or F2 coupled (see this ) HSQC type experiments, thus making the fitting problem underdetermined. Armando Navarro et al. have recently proposed an elegant approach to get the most out of the experimental data by incorporating into the calculations two of the most common freely rotating groups, namely the methyl and phenyl groups (using 2-fold and 3-fold jump models).

The authors have automated this averaging of RDCs from freely rotating groups in version 1.03 of our program Mspin which we hope will facilitate the use of RDC among a broader community of users interested in solving structural questions of small molecules