MA’AT: A Web-Based Application to Determine Rotamer Population Distributions in Solution from Nuclear Magnetic Resonance Spin-Coupling Constants

Abstract

A hybrid experimental−computational method to determine conformational equilibria of molecules in solution has been developed based on the use of redundant nuclear magnetic resonance (NMR) spin−spin coupling constants (spin-couplings; Jcouplings), density functional theory (DFT) calculations, and circular statistics. The mathematics that underpins the method, known as MA'AT analysis, is presented, and key components of a computer program that applies this algorithm are discussed. The method was tested using single-state and multi-state models to identify the factors required to obtain reliable results, to establish the limitations of the method, and to highlight techniques to evaluate the uniqueness of solution.

One-Bond 13C–1H and 13C–13C Spin-Coupling Constants as Constraints in MA’AT Analysis of Saccharide Conformation

“…The effect on the mean value of ω was small (<2°), and the standard errors of the mean values were smaller when 1 J values were included in the analyses. CSDs and their errors responded more randomly to the inclusion of 1 J values, consistent with prior observations indicating greater sensitivity of CSDs and their errors to the nature of the model being fit (i.e., single- or multistate) and the types of J -values included in the fit . In general, the inclusion of 1 J CH and/or 1 J CC values in MA’AT analyses of ω in 1 – 3 gave models that were similar to those obtained when these values were excluded, indicating that DFT-calculated 1 J CH and 1 J CC values are sufficiently close to the true values to permit their use in MA’AT analyses when secondary structural factors are known in the experimental compounds, and when these effects can be treated properly in the DFT calculations.…”

“…A User’s Manual is available on the application’s webpage. The details of MA’AT analysis and use of the MA’AT program have been reported recently …”

“…The details of MA'AT analysis and use of the MA'AT program have been reported recently. 41 Aqueous Molecular Dynamics Simulations of 1 c −3 c . Initial structures of 1 c −3 c were built using the Carbohydrate Builder module available at the GLYCAM web site (http:// www.glycam.org).…”

One-Bond 13C-13C Spin-Coupling Constants in Saccharides: A Comparison of Experimental and Calculated Values By Density Functional Theory Using Solid-State 13C NMR and X-Ray Crystallography

“…X-Ray crystallography and solid-state 13 C NMR spectroscopy have been used synergistically to determine the structural properties of carbohydrates in solution by addressing some of the limitations discussed above. [19][20][21][22][23][24] MA'AT analysis, [35][36][37][38][39][40][41] a new experimental method to model molecular conformation in solution, combines DFT calculations and experimental NMR J-couplings to give probability distributions of molecular torsion angles in solution. MA'AT probability distributions are superimposable on those obtained by MD simulation, allowing direct comparisons of experimental and calculated models.…”

“…MA'AT probability distributions are superimposable on those obtained by MD simulation, allowing direct comparisons of experimental and calculated models. [35][36][37][38][39][40][41] The method uses 2 J and 3 J values primarily to model various conformational elements in saccharides (e.g., O-glycosidic linkages, [35][36][37] ring conformation, 39 side-chain conformation 38,41 ). To extend MA'AT analysis to multi-state models, it would be useful to employ 1 J CC and 1 J CH values as inputs due to their high abundance in saccharides and their attractive conformational properties (e.g., large dynamic ranges).…”