Configuration determination by residual dipolar couplings: accessing the full conformational space by molecular dynamics with tensorial constraints

Abstract

The use of tensorial orientational constraints for NMR-derived residual dipolar couplings (RDCs) in molecular dynamics simulations brings detailed structural models of flexible molecules in solution in reach.

Determination of Configuration and Conformation of a Reserpine Derivative with Seven Stereogenic Centers Using Molecular Dynamics with RDC‐Derived Tensorial Constraints**

“…However, no absolute evaluation of the fulfillment of experimental constraints is possible. This can be much better achieved by the previously introduced quality factor (n/χ 2 ), [6c] which is explained further in the experimental section and has been used throughout the manuscript. A structural model that fully complies with experimental data within the experimental error must result in n/χ 2 >1; consequently, a value below 1 is a clear indication that at least one experimental value is outside its corresponding experimental error.…”

“…The program package COSMOS has a specialized protocol for time averaged molecular dynamics (MD) simulations with orientational constraints and also includes a molecular mechanics force field [6c, 22] . The orientation encoded in tensorial constraints derived from experimental RDC values is used as a factor for the generation of pseudo forces, which constrain the orientation of the molecule within the MD (for details of the approach see Tzvetkova et al [6c] …”

“…Based on analytical solutions for the first and second derivative of the tensor with respect to the laboratory frame axes x , y and z , the MDOC run will rotate individual C−H bond vectors to improve the overall pseudo energy depending on the difference between each calculated and experimental RDC. For a successful MD run, different parameters have to be optimized, like the strength of pseudo forces ( k ) and the alignment scaling factor ( s AM ), which reduces the calculation time by avoiding unnecessary computation of isotropic tumbling of the molecule of interest [6c] . In the optimized runs, we set k to 5.5.10 −4 and s AM to 4.10 −3 to obtain calculated RDC values in the range of 1 D CH =−25.6 to 32.1 Hz (see Table 3 for the individual values).…”

“…Several implementations have been reported based on an approximated alignment tensor as initial input [25] . An alignment tensor for a flexible molecule, however, is per se ill‐defined and the recently published MDOC approach seems far more appropriate in this case [6c, 7a] …”

Probing Long‐Range Anisotropic Interactions: a General and Sign‐Sensitive Strategy to Measure 1H–1H Residual Dipolar Couplings as a Key Advance for Organic Structure Determination

“…We expect it to find wide application within, for instance, natural‐product configuration determination, enantiomeric‐excess determination, or conformational analysis of organic compounds. Experimental sign determination especially opens the door for use of 1 H– 1 H RDCs in flexible molecules, where signs cannot simply be back‐calculated from one‐bond RDCs. Ideally, one alignment tensor per chiral element can be determined, such that local tensors, which allow relating these stereogenic elements, become routinely accessible .…”