A Test of the Single-Conformation Hypothesis in the Analysis of NMR Data for Small Polar Molecules:  A Force Field Comparison

Abstract

A tricyclic ketone with seven stereogenic centers produced in >95:5 diastereomeric excess by an asymmetric Diels-Alder reaction has been subjected to a careful 2-D NMR(CDCl 3 )/MD analysis by Reggelin and co-workers and interpreted in terms of a single conformation in CDCl 3 solution. The present work examines the validity of this interpretation. Specifically, the conformational profile of the endo isomer of the tricyclic ketone was examined by Monte Carlo searches with both the MM2* and MMFF force fields in MacroModel using the GB/SA CHCl 3 solvent continuum model. The two sets of conformations were then combined and optimized with the MM3(96) force field. The structures of the resulting conformations and the NMR-derived geometric variables were together subjected to a NAMFIS analysis (NMR analysis of molecular flexibility in solution). Ideally, the procedure deconvolutes the thermally averaged NMR data into a small family of conformations that optimally represents the J-derived torsions and the NOE-derived distances. It is concluded that the tricyclic ketone under study is not well-characterized by a single conformation in CDCl 3 solution, but by a set of rapidly equilibrating conformers that produces a deceptively averaged NMR spectrum. It would appear that the previously suggested structure is a virtual conformation obligated to compress multiconformer features into a single 3-D construct. In additon, we find that current force fields do not uniformly represent the conformational profile of polar molecules such as 1. The cause is traced primarily to the variable treatment of electrostatic effects.

Dynamics of the Glycosidic Bond: Conformational Space of Lactose

“…The poor fit of these ensembles is well explained by the known uncertainties of the energies of conformations derived by computation. [35] Such methods provide ensembles encompassing the geometries present in solutions along with a large number of additional, theoretically possible conformations, which in reality may have zero probabilities. [36] Hence, theoretical conformational pools allow the identification of solution geometries when utilised in combination with even sparse experimental data.…”

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

“…This value commonly falls below 200 and sometimes below 100. 17,18,25 However, the significance of the present value is underscored by the fact that similar NAMFIS processing of the previously proposed family of conformers alone gives a SSD of 103. The relatively much lower SSD of 57 establishes the stated goal of the NAMFIS analysis to produce multiple families of diverse conformations which fit the data better than any single family.…”

“…17,18,22 NAMFIS uses a set of three-bond 3 J HÀ ÀH proton-proton coupling constants and interproton distances calculated for a set of molecular conformations from a comprehensive conformational search. In this case, the Karplus equation used for the calculation of the 3 J HÀ ÀNÀ ÀCÀ ÀH coupling constants was the one derived by Pardi et al 43 The interproton distances are calculated using r 26 averaging and a reference distance standard, the 1.8 Å distance between geminal methylene protons.…”

“…However, an alternative view suggests that the stevastelins with nine rotatable bonds in their backbone may represent more conformational diversity than suggested in the recent analysis and may populate motifs in solution that are dissimilar from the ones proposed. To deconvolute the average NMR data and reveal the individual conformational components that contribute to it, we have combined the NMR variables cited in the report with extensive multiple force field conformational searches and have performed a joint computational-NMR analysis using NAMFIS 17,18 (NMR Analysis of Molecular Flexibility In Solution, described in ''Methods" section).…”

C‐3′‐Cyclopropanated Taxol Analogs: Synthesis, Bioassay and Biostructural Analysis

“…The combination of a 2D NMR NOESY or ROESY experiment, an exhaustive conformational analysis and a NAMFIS (NMR analysis of molecular flexibility in solution) [41,42] deconvolution of the averaged NMR spectrum provided minimum-energy conformers assigned specific populations in the dynamic conformational equilibrium. In all these cases involving active taxanes, T-forms were found among the set of solution conformations and presumed to serve as the bioactive forms.…”