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marine drugs Article Model-Free Approach for the Configurational Analysis of Marine Natural Products † Matthias Köck 1,* , Michael Reggelin 2 and Stefan Immel 2,* 1 Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research, Am Handelshafen 12, 27570 Bremerhaven, Germany 2 Clemens-Schöpf-Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Alarich-Weiss-Straße 4, 64287 Darmstadt, Germany; [email protected] * Correspondence: [email protected] (M.K.); [email protected] (S.I.) † Dedicated to Prof. Dr. Horst Kessler on occasion of his 81st birthday. Abstract: The NMR-based configurational analysis of complex marine natural products is still not a routine task. Different NMR parameters are used for the assignment of the relative configuration: NOE/ROE, homo- and heteronuclear J couplings as well as anisotropic parameters. The combined distance geometry (DG) and distance bounds driven dynamics (DDD) method allows a model-free approach for the determination of the relative configuration that is invariant to the choice of an initial starting structure and does not rely on comparisons with (DFT) calculated structures. Here, we will discuss the configurational analysis of five complex marine natural products or synthetic derivatives thereof: the cis-palau’amine derivatives 1a and 1b, tetrabromostyloguanidine (1c), plakilactone H (2), and manzamine A (3). The certainty of configurational assignments is evaluated in view of the accuracy of the NOE/ROE data available. These case studies will show the prospective breadth of application of the DG/DDD method. Citation: Köck, M.; Reggelin, M.; Keywords: configurational analysis; distance geometry; distance bounds driven dynamics; NMR Immel, S. Model-Free Approach for spectroscopy; NOE data the Configurational Analysis of Marine Natural Products . Mar. Drugs 2021, 19, 283. https://doi.org/ 10.3390/md19060283 1. Introduction The determination of the relative configuration of marine natural products usually Academic Editor: Bill J. Baker follows the constitutional structure elucidation. Despite numerous attempts, there is so far no standard or even automated protocol for the configurational and conformational Received: 8 April 2021 assignment of natural products or small organic molecules in general [1–14]. Although Accepted: 11 May 2021 recently, the application of anisotropic NMR data, such as residual dipolar couplings Published: 21 May 2021 (RDCs) or residual chemical shift anisotropy (RCSA), has become more and more popular, the cross-relaxation (NOE or ROE) from which interproton distances can be obtained is Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in still a major source of structural information. The use of NOE- or ROE-derived inter- published maps and institutional affil- proton distances for the configurational analysis is a mature technique [15,16] that can iations. be amended by including RDCs in restrained distance geometry (rDG) simulations in a protocol that we have discussed in detail very recently [17]. Herein, we will concentrate on the NOE/ROE-restrained distance geometry [18–20] and distance bounds driven dynamics method (rDG/DDD) [21,22], which is, from our point of view, the method of choice for the configurational analysis of small organic molecules with several stereogenic centers [23–28]. Copyright: © 2021 by the authors. The use of interproton distances from NOESY spectra as restraints in molecular dynamics Licensee MDPI, Basel, Switzerland. This article is an open access article simulations (rMD) was introduced about 35 years ago [29,30] and since then, it has been distributed under the terms and a successful method for the NMR-based conformational analysis of biomacromolecules. conditions of the Creative Commons The DDD approach was later applied as a method for “shaking up” the structures before Attribution (CC BY) license (https:// starting the rMD analysis [21,22]. The concept of floating chirality (fc) was added to aid the creativecommons.org/licenses/by/ assignment of diastereotopic protons or methyl groups in proteins, and was first applied in 4.0/). 1988 to distance geometry (DG) calculations [31] and in 1989 to rMD simulations [32]. The Mar. Drugs 2021, 19, 283. https://doi.org/10.3390/md19060283 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2021, 19, x FOR PEER REVIEW 2 of 15 Mar. Drugs 2021, 19, 283 2 of 15 was first applied in 1988 to distance geometry (DG) calculations [31] and in 1989 to rMD simulationsmost important [32]. aspect The most of the important rDG/DDD aspect method of the is therDG/DDD possibility method to allow is the configurations possibility to to allowdynamically configurations change duringto dynamically the simulation change (floating during chirality, the simulation fc) and therefore(floating tochirality, determine fc) andthe conformationtherefore to determine and the relative the conformation configuration and of smallthe relative organic configuration molecules, simultaneously of small or- ganic(fc-rDG/DDD). molecules, simultaneously (fc-rDG/DDD). ThisThis approach approach combines combines distance distance geometry geometry (DG) (DG) [18–20] [18–20] and and dist distanceance bounds bounds driven driven dynamicsdynamics (DDD) (DDD) [21,22], [21,22], using NOE/ROE-derivedNOE/ROE-derived distances distances as as restraints restraints [23–28]. [23–28]. The The generalgeneral workflow workflow of of the the DG/DDD DG/DDD method method is is repr representedesented in in Figure Figure 11.. Similar to using aa molecularmolecular model model construction construction kit, kit, molecular molecular ge geometriesometries are are generated generated within within the the limits limits of holonomicof holonomic distance distance bounds bounds (relations (relations between between positional positional coordinates), coordinates), derived derived from from the constitutionthe constitution and experimental and experimental distance distance margins margins deduced deduced from NMR from NMRdata. As data. this As step this a usesstep distances a uses distances only, and only, all and implied all implied informatio informationn on angles on angles and torsions and torsions is actually is actually dis- carded,discarded, it is it ensured is ensured that that the the structures structures gene generatedrated are are not not biased biased by by the the input input structure; structure; modelsmodels of of all all possible possible configurations configurations and and conf conformationsormations are are generated generated with with purely purely statis- sta- ticaltistical weights. weights. In order In order to add to additional add additional degrees degrees of freedom of freedom to this to building this building process process (“me- trization”),(“metrization”), it is carried it is carried out in out four-dimensional in four-dimensional (4D) Cartesian (4D) Cartesian space. space.These Theseinitial guess initial modelsguess models (Figure (Figure 1b) are1 )then are thenrefined refined by a sequence by a sequence of 4D of and 4D 3D and simulated 3D simulated annealing annealing sim- ulationssimulations (DDD) (DDD) where where at each at each step, step, the squared the squared violations violations of experimental of experimental restraints restraints are computedare computed as a dimensionless as a dimensionless pseudo pseudo energy energy (total error) (total error)with empirically with empirically chosen chosen“force constants”.“force constants”. In all Indynamics all dynamics and andoptimization optimization calculatio calculations,ns, the the partial partial derivatives ¶E /¶rα (α 2 x, y, z(, w) for all atoms) of this pseudo energy term, with respect to 4D ∂Etotaltotal/∂rα (α∈x,y,z(,w) for all atoms) of this pseudo energy term, with respect to 4D and 3Dand Cartesian 3D Cartesian atomic atomic coordinate coordinates,s, are interpreted are interpreted and used and as used forces as governing forces governing the evolu- the tionevolution of the of system; the system; a detailed a detailed description description of this of this procedure procedure is isgiven given in in Refs. Refs. [17,21,22]. [17,21,22]. Finally,Finally, all emergent structuresstructures areare rankedranked and and sorted sorted by by their their pseudo pseudo energies energies (total (total error; er- ror;sum sum of total of total violations), violations), and and the lowerthe lower this “energy”this “energy” becomes, becomes, the more the more likely likely the corre- the correspondingsponding molecular molecular geometry geometry represents represents the correct the configurationcorrect configuration (and conformation) (and confor- of mation)the compound of the compound under investigation under investigation (Figure1). (Figure Note that 1a). at Note any pointthat at of any any point rDG/DDD of any rDG/DDDsimulation, simulation, neither a conventionalneither a conventional parametrized parametrized force-field force-field is involved, is involved, nor are any nor pre-are anysumptions presumptions on conformational on conformational preferences preferences implied, butimplied, all molecular but all structuresmolecular and structures relative configurations of stereogenic centers evolve solely on the basis of experimental NMR data and relative configurations of stereogenic centers evolve solely on the basis of experi- (Figure1, Steps b and c). mental NMR data (Figure 1, Steps b and c). FigureFigure 1. 1. WorkflowWorkflow of of fc-rDG/DDD fc-rDG/DDD calculations: calculations: (a ()a based) based on
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