Residual Dipolar Couplings in Structure Determination of Natural Products

The determination of natural products stereochemistry remains a formidable task.Residual dipolar couplings(RDCs)induced by anisotropic media are a powerful tool for determination of the stereochemistry of organic molecule in solution.This review will provide a short introduction on RDCs-based methodology for the structural elucidation of natural products.Special attention is given to the current availability of alignment media in organic solvents.The applications of RDCs for structural analysis of some examples of natural products were discussed and summarized.Graphical Abstract This review provides a short introduction on RDCs-based methodology for the structural elucidation of natural products.Special attention is given to the current availability of alignment media in organic solvents.The applications of RDCs for structural analysis of some examples of natural products were discussed and summarized.

On the use of residual dipolar couplings in multi-state structure calculation of two-domain proteins

Residual dipolar couplings(RDCs)are powerful nuclear magnetic resonance(NMR)probes for the structure calculation of biomacromolecules.Typically,an alignment tensor that defines the orientation of the entire molecule relative to the magnetic field is determined either before refinement of individual bond vectors or simultaneously with this refinement.For single-domain proteins this approach works well since all bond vectors can be described within the same coordinate frame,which is given by the alignment tensor.However,novel approaches are sought after for systems where no universal alignment tensor can be used.Here,we present an approach that can be applied to two-domain proteins that enables the calculation of multiple states within each domain as well as with respect to the relative positions of the two domains.

The Use of a Combination of RDC and Chiroptical Spectroscopy for Determination of the Absolute Configuration of Fusariumin A from the Fungus Fusarium sp.

A new alkylpyrrole derivative,fusariumin A(1),was isolated from the culture broth of the fungus Fusarium sp.The absolute configuration of fuasiumin A has been established as(2'R,3'R)using a combination of RDC(residual dipolar coupling)-based NMR and DFT-supported chiroptical spectroscopy.It is worth to note that in this study without the aid of the RDC analysis,an unambiguous determination of configuration and conformation was not feasible due to the excessive conformational possibilities of this open-chain compound.

Sensitivity-enhanced Experiments for the Measurement of J and Dipolar Coupling Constants

A sensitivity-enhanced IPAP NMR experiment was described in this paper, whichseparates the ~1H-^(15)N doublets into two different spectra to alleviate the problem of resonanceoverlaps and achieve the accurate measurement of J and residual dipolar coupling constants inproteins. This experiment offered 20%―60% sensitivity enhancement over the original IPAPexperiment, and therefore produced more measurable resonances. Pulsed field gradient was used forcoherence selection. Water-flip-back approach was used for water suppression. Thesensitivity-enhanced IPAP experiment was employed in the measurement of ~1J_(NH) and ~1D_(NH)constants of the protein UBC9.

Algorithmic challenges in structure-based drug design and NMR structural biology

The three-dimensional structure of a biomolecule rather than its one-dimensionM sequence determines its biological function. At present, the most accurate structures are derived from experimental data measured mainly by two techniques： X-ray crystallog- raphy and nuclear magnetic resonance （NMR） spec- troscopy. Because neither X-ray crystallography nor NMR spectroscopy could directly measure the positions of atoms in a biomolecule, algorithms must be designed to compute atom coordinates from the data. One salient feature of most NMR structure computation algorithms is their reliance on stochastic search to find the lowest energy conformations that satisfy the experimentally- derived geometric restraints. However, neither the cor- rectness of the stochastic search has been established nor the errors in the output structures could be quantified. Though there exist exact algorithms to compute struc- tures from angular restraints, similar algorithms that use distance restraints remain to be developed. An important application of structures is rational drug design where protein-ligand docking plays a crit- ical role. In fact, various docking programs that place a compound into the binding site of a target protein have been used routinely by medicinal chemists for both lead identification and optimization. Unfortunately, de- spite ongoing methodological advances and some success stories, the performance of current docking algorithms is still data-dependent. These algorithms formulate the docking problem as a match of two sets of feature points. Both the selection of feature points and the search for the best poses with the minimum scores are accomplished through some stochastic search methods. Both the un- certainty in the scoring function and the limited sam- pling space attained by the stochastic search contribute to their failures. Recently, we have developed two novel docking algorithms： a data-driven docking algorithm and a general docking algorithm that does not rely on experimental data. Our algorithms search the pose space exhaustively with the pose space itself being limited to a set of hierarchical manifolds that represent, respectively, surfaces, curves and points with unique geometric and energetic properties. These algorithms promise to be es- pecially valuable for the docking of fragments and small compounds as well as for virtual screening.

Generation of Accelerated Stability Experiment Profile of Inertial Platform Based on Finite Element

The residual stress generated in the manufacturing process of inertial platform causes the drift of inertial platform parameters in long-term storage condition.However,the existing temperature cycling experiment could not meet the increased repeatability technical requirements of inertial platform parameters.In order to solve this problem,in this paper,firstly the Unigraphics（UG） software and the interface compatibility of ANSYS software are used to establish the inertial platform finite element model.Secondly,the residual stress is loaded into finite element model by ANSYS function editor in the form of surface loads to analyze the efficiency.And then,the generation based on ANSYS simulation inertial platform to accelerate the stability of experiment profile is achieved by the application of the analysis method of orthogonal experimental design and ANSYS thermal-structural coupling.The optimum accelerated stability experiment profile is determined finally,which realizes the rapid,effective release of inertial platform residual stress.The research methodology and conclusion of this paper have great theoretical and practical significance to the production technology of inertial platform.