Skeletal and Mechanistic Diversity in Ir-Catalyzed Cycloisomerizations of Allene-Tethered Pyrroles and Indoles.

Pyrroles and indoles bearing N-allenyl tethers participate in a variety of iridium-catalyzed cycloisomerization processes initiated by a C-H activation step, to deliver a diversity of synthetically relevant azaheterocyclic products. By appropriate selection of the ancillary ligand and the substitution pattern of the allene, the reactions can diverge from simple intramolecular hydrocarbonations to tandem processes involving intriguing mechanistic issues. Accordingly, a wide range of heterocyclic structures ranging from dihydro-indolizines and pyridoindoles to tetrahydroindolizines, as well as cyclopropane-fused tetrahydroindolizines can be obtained. Moreover, by using chiral ligands, these cascade processes can be carried out in an enantioselective manner. DFT studies provide insights into the underlying mechanisms and justify the observed chemo- regio- and stereoselectivities.

Unlocking the specificity of antimicrobial peptide interactions for membrane-targeted therapies.

Antimicrobial peptides (AMPs) are increasingly recognized as potent therapeutic agents, with their selective affinity for pathological membranes, low toxicity profile, and minimal resistance development making them particularly attractive in the pharmaceutical landscape. This study offers a comprehensive analysis of the interaction between specific AMPs, including magainin-2, pleurocidin, CM15, LL37, and clavanin, with lipid bilayer models of very different compositions that have been ordinarily used as biological membrane models of healthy mammal, cancerous, and bacterial cells. Employing unbiased molecular dynamics simulations and metadynamics techniques, we have deciphered the intricate mechanisms by which these peptides recognize pathogenic and pathologic lipid patterns and integrate into lipid assemblies. Our findings reveal that the transverse component of the peptide's hydrophobic dipole moment is critical for membrane interaction, decisively influencing the molecule's orientation and expected therapeutic efficacy. Our approach also provides insight on the kinetic and dynamic dependence on the peptide orientation in the axial and azimuthal angles when coming close to the membrane. The aim is to establish a robust framework for the rational design of peptide-based, membrane-targeted therapies, as well as effective quantitative descriptors that can facilitate the automated design of novel AMPs for these therapies using machine learning methods.

Human O-GlcNAcase Uses a Preactivated Boat-skew Substrate Conformation for Catalysis. Evidence from X-ray Crystallography and QM/MM Metadynamics.

Human O-linked ß-N-acetylglucosaminidase (hOGA) is one of the two enzymes involved in nuclear and cytoplasmic protein O-GlcNAcylation, an essential post-translational modification. The enzyme catalyzes the hydrolysis of the GlcNAc-O-(Ser/Thr) glycosidic bonds via anchimeric assistance through the 2-acetamido group of the GlcNAc sugar. However, the conformational itinerary of the GlcNAc ring during catalysis remains unclear. Here we report the crystal structure of wild type hOGA in complex with a nonhydrolyzable glycopeptide substrate and elucidate the full enzyme catalytic mechanism using QM/MM metadynamics. We show that the enzyme can bind the substrate in either a chair- or a boat-like conformation, but only the latter is catalytically competent, leading to the reaction products via 1,4B/1S3 → [4E]‡ → 4C1 and 4C1 → [4E]‡ → 1,4B/1S3 conformational itineraries for the first and second catalytic reaction steps, respectively. Our results reconcile previous experimental observations for human and bacterial OGA and will aid the development of more effective OGA inhibitors for diseases associated with impaired O-GlcNAcylation.

Uncovering the mechanisms of cyclic peptide self-assembly in membranes with the chirality-aware MA(R/S)TINI forcefield.

Cyclic peptides (CPs) formed by alternation of D- and L-amino acids (D,L-CPs) can self-assemble into nanotubes (SCPNs) by parallel or/and antiparallel stacking. Different applications have been attributed to these nanotubes, including the disruption of lipid bilayers of specific compositions and the selective transport of ions throughout membranes. Molecular dynamics (MD) simulations have significantly contributed to understand the interaction between CPs, including the structural, dynamic and transport properties of their supramolecular aggregates. The high computational cost of atomic resolution forcefields makes them impractical for simulating the self-assembly of macromolecules, so coarse-grained (CG) models might represent a more feasible solution for this purpose. However, general CG models used for the simulation of biomolecules such as the MARTINI forcefield do not explicitly consider the non-covalent interactions leading to the formation of secondary structure patterns in proteins. This becomes particularly important in the case of CPs due to the D- and L-chirality alternation in their sequence, leading to opposite orientations of the backbone polar groups on both sides of the cyclic ring plane. In order to overcome this limitation, we have extended the MARTINI forcefield to introduce chirality in each residue of the CPs. The new parametrization, which we have called MA(R/S)TINI, reproduces the expected self-assembly patterns for several CP sequences in the presence of different membrane models, explicitly considering the chirality of the CPs and with no significant extra computational cost. Our simulations provide new mechanistic information of how these systems self-assemble in presence of different lipid scenarios, showing that the CP-CP and CP-membrane interactions are sensitive to the peptide sequence chirality. This opens the door to design new bioactive CPs based on CG-MD simulations. A web-based tool for the automatic parameterization of new CP sequences using MA(R/S)TINI, among other functionalities, is under construction (see http://cyclopep.com).

Molecular Dynamics Simulations of Transmembrane Cyclic Peptide Nanotubes Using Classical Force Fields, Hydrogen Mass Repartitioning, and Hydrogen Isotope Exchange Methods: A Critical Comparison.

Self-assembled cyclic peptide nanotubes with alternating D- and L-amino acid residues in the sequence of each subunit have attracted a great deal of attention due to their potential for new nanotechnology and biomedical applications, mainly in the field of antimicrobial peptides. Molecular dynamics simulations can be used to characterize these systems with atomic resolution at different time scales, providing information that is difficult to obtain via wet lab experiments. However, the performance of classical force fields typically employed in the simulation of biomolecules has not yet been extensively tested with this kind of highly constrained peptide. Four different classical force fields (AMBER, CHARMM, OPLS, and GROMOS), using a nanotube formed by eight D,L-α-cyclic peptides inserted into a lipid bilayer as a model system, were employed here to fill this gap. Significant differences in the pseudo-cylindrical cavities formed by the nanotubes were observed, the most important being the diameter of the nanopores, the number and location of confined water molecules, and the density distribution of the solvent molecules. Furthermore, several modifications were performed on GROMOS54a7, aiming to explore acceleration strategies of the MD simulations. The hydrogen mass repartitioning (HMR) and hydrogen isotope exchange (HIE) methods were tested to slow down the fastest degrees of freedom. These approaches allowed a significant increase in the time step employed in the equation of the motion integration algorithm, from 2 fs up to 5-7 fs, with no serious changes in the structural and dynamical properties of the nanopores. Subtle differences with respect to the simulations with the unmodified force fields were observed in the concerted movements of the cyclic peptides, as well as in the lifetime of several H-bonds. All together, these results are expected to contribute to better understanding of the behavior of self-assembled cyclic peptide nanotubes, as well as to support the methods tested to speed up general MD simulations; additionally, they do provide a number of quantitative descriptors that are expected to be used as a reference to design new experiments intended to validate and complement computational studies of antimicrobial cyclic peptides.

Palladium-Catalyzed Tandem Cycloisomerization/Cross-Coupling of Carbonyl- and Imine-Tethered Alkylidenecyclopropanes.

Pd0 catalysts featuring phosphorus-based monodentate ligands can detour the reactivity of carbonyl-tethered alkylidenecyclopropanes (ACPs) from standard (3+2) cycloadditions towards tandem cycloisomerization/cross-coupling processes. This new reactivity lies on the formation of key π-allyl oxapalladacyclic intermediates, which are subsequently trapped with external nucleophilic partners, instead of undergoing canonical C-O reductive eliminations. Importantly, the use of imine-tethered ACP's is also feasible. Therefore, the method provides a straightforward and stereoselective entry to a wide variety of highly functionalized cyclic alcohols and amines.

SuPepMem: A database of innate immune system peptides and their cell membrane interactions.

Host defense peptides (HDPs) are short cationic peptides that play a key role in the innate immune response of all living organisms. Their action mechanism does not depend on the presence of protein receptors, but on their ability to target and disrupt the membranes of a wide range of pathogenic and pathologic cells which are recognized by their specific compositions, typically with a relatively high concentration of anionic lipids. Lipid profile singularities have been found in cancer, inflammation, bacteria, viral infections, and even in senescent cells, enabling the possibility to use them as therapeutic targets and/or diagnostic biomarkers. Molecular dynamics (MD) simulations are extraordinarily well suited to explore how HDPs interact with membrane models, providing a large amount of qualitative and quantitative information that, nowadays, cannot be assessed by wet-lab methods at the same level of temporal and spatial resolution. Here, we present SuPepMem, an open-access repository containing MD simulations of different natural and artificial peptides with potential membrane lysis activity, interacting with membrane models of healthy mammal, bacteria, viruses, cancer or senescent cells. In addition to a description of the HDPs and the target systems, SuPepMem provides both the input files necessary to run the simulations and also the results of some selected analyses, including structural and MD-based quantitative descriptors. These descriptors are expected to be useful to train machine learning algorithms that could contribute to design new therapeutic peptides. Tools for comparative analysis between different HDPs and model membranes, as well as to restrict the queries to structural and time-averaged properties are also available. SuPepMem is a living project, that will continuously grow with more simulations including peptides of different sequences, MD simulations with different number of peptide units, more membrane models and also several resolution levels. The database is open to MD simulations from other users (after quality check by the SuPepMem team). SuPepMem is freely available under https://supepmem.com/.

Transmembrane Self-Assembled Cyclic Peptide Nanotubes Based on α-Residues and Cyclic δ-Amino Acids: A Computational Study.

Self-assembling cyclic peptide nanotubes have been shown to function as synthetic, integral transmembrane channels. The combination of natural and nonnatural aminoacids in the sequence of cyclic peptides enables the control not only of their outer surface but also of the inner cavity behavior and properties, affecting, for instance, their permeability to different molecules including water and ions. Here, a thorough computational study on a new class of self-assembling peptide motifs, in which δ-aminocycloalkanecarboxylic acids are alternated with natural α-amino acids, is presented. The presence of synthetic δ-residues creates hydrophobic regions in these α,δ-SCPNs, which makes them especially attractive for their potential implementation in the design of new drug or diagnostic agent carrier systems. Using molecular dynamics simulations, the behavior of water molecules, different ions (Li+, Na+, K+, Cs+, and Ca2+), and their correspondent counter Cl- anions is extensively investigated in the nanoconfined environment. The structure and dynamics are mutually combined in a diving immersion inside these transmembrane channels to discover a fascinating submarine nanoworld where star-shaped water channels guide the passage of cations and anions therethrough.

Highly Enantioselective Iridium(I)-Catalyzed Hydrocarbonation of Alkenes: A Versatile Approach to Heterocyclic Systems Bearing Quaternary Stereocenters.

We report a versatile, highly enantioselective intramolecular hydrocarbonation reaction that provides a direct access to heteropolycyclic systems bearing chiral quaternary carbon stereocenters. The method, which relies on an iridium(I)/bisphosphine chiral catalyst, is particularly efficient for the synthesis of five-, six- and seven-membered fused indole and pyrrole products, bearing one and two stereocenters, with enantiomeric excesses of up to >99 %. DFT computational studies allowed to obtain a detailed mechanistic profile and identify a cluster of weak non-covalent interactions as key factors to control the enantioselectivity.

Effect of Water Models on Transmembrane Self-Assembled Cyclic Peptide Nanotubes.

Self-assembling cyclic peptide nanotubes can form nanopores when they are inserted in lipid bilayers, acting as ion and/or water permeable channels. In order to improve the versatility of these systems, it is possible to specifically design cyclic peptides with a combination of natural and non-natural amino acids, enabling the control of the nature of the inner cavity of the channels. Here, the behavior of two types of self-assembling peptide motifs, alternating α-amino acids with γ- or δ-aminocycloalkanecarboxylic acids, is studied via molecular dynamics (MD) simulations. The behavior of water molecules in nanopores is expected to affect the properties of these channels and therefore merits detailed examination. A number of water models commonly used in MD simulations have been validated by how well they reproduce bulk water properties. However, it is less clear how these water models behave in the nanoconfined condition inside a channel. The behavior of four different water models-TIP3P, TIP4P, TIP4P/2005, and OPC-are evaluated in MD simulations of self-assembled cyclic peptide nanotubes of distinct composition and diameter. The dynamic behavior of the water molecules and ions in these designed artificial channels depends subtly on the water model used. TIP3P water molecules move faster than those of TIP4P, TIP4P/2005, and OPC. This demeanor is clearly observed in the filling of the nanotube, in water diffusion within the pore, and in the number and stability of hydrogen bonds of the peptides with water. It was also shown that the water model influences the simulated ion flux through the nanotubes, with TIP3P producing the greatest ion flux. Additionally, the two more recent models, TIP4P/2005 and OPC, which are known to reproduce the experimental self-diffusion coefficient of bulk water quite well, exhibit very similar results under the nanoconfined conditions studied here. Because none of these models have been parametrized specifically for waters confined in peptide nanotubes, this study provides a point of reference for further validation.

An immersive journey to the molecular structure of SARS-CoV-2: Virtual reality in COVID-19.

The era of the explosion of immersive technologies has bumped head-on with the coronavirus disease 2019 (COVID-19) global pandemic caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The proper understanding of the three-dimensional structures that compose the virus, as well as of those involved in the infection process and in treatments, is expected to contribute to the advance of fundamental and applied research against this pandemic, including basic molecular biology studies and drug design. Virtual reality (VR) is a powerful technology to visualize the biomolecular structures that are currently being identified for SARS-CoV-2 infection, opening possibilities to significant advances in the understanding of the disease-associate mechanisms and thus to boost new therapies and treatments. The present availability of VR for a large variety of practical applications together with the increasingly easiness, quality and economic access of this technology is transforming the way we interact with digital information. Here, we review the software implementations currently available for VR visualization of SARS-CoV-2 molecular structures, covering a range of virtual environments: CAVEs, desktop software, and cell phone applications, all of them combined with head-mounted devices like cardboards, Oculus Rift or the HTC Vive. We aim to impulse and facilitate the use of these emerging technologies in research against COVID-19 trying to increase the knowledge and thus minimizing risks before placing huge amounts of money for the development of potential treatments.

Membrane targeting antimicrobial cyclic peptide nanotubes - an experimental and computational study.

The search of new antibiotics, particularly with new mechanisms of action, is nowadays a very important public health issue, due to the worldwide increase of resistant pathogens. Within this effort, much research has been done on antimicrobial peptides, because having the membrane as a target, they represent a new antibiotic paradigm. Among these, cyclic peptides (CPs) made of sequences of D- and L-amino acids have emerged as a new class of potential antimicrobial peptides, due to their expected higher resistance to protease degradation. These CPs are planar structures that can form Self-assembled Cyclic Peptide Nanotubes (SCPNs), in particular in the presence of lipid membranes. Aiming at understanding their mechanism of action, we used biophysical experimental techniques (DSC and ATR-FTIR) together with Coarse-grained molecular dynamics (CG-MD) simulations, to characterize the interaction of these CPs with model membranes of different electrostatic charges' contents. DSC results revealed that the CPs show a strong interaction with negatively charged membranes, with differences in the strength of interactions depending on peptide and on membrane charge content, at odds with no or mild interactions with zwitterionic membranes. ATR-FTIR suggested that the peptides self-assemble at the membrane surface, adopting mainly a ß-structure. The experiments with polarized light showed that in most cases they lie parallel to the membrane surface, but other forms and orientations are also apparent, depending on peptide structure and lipid:peptide ratio. The nanotube formation and orientation, as well as the dependence on membrane charge were also confirmed by the CG-MD simulations. These provide detail on the position and interactions, in agreement with the experimental results. Based on the findings reported here, we could proceed to the design and synthesis of a second-generation CPs, based on CP2 (soluble peptide), with increased activity and reduced toxicity.

The Lord of the NanoRings: Cyclodextrins and the battle against SARS-CoV-2.

A handful of singular structures and laws can be observed in nature. They are not always evident but, once discovered, it seems obvious how to take advantage of them. In chemistry, the discovery of reproducible patterns stimulates the imagination to develop new functional materials and technological or medical applications. Two clear examples are helical structures at different levels in biological polymers as well as ring and spherical structures of different size and composition. Rings are intuitively observed as holes able to thread elongated structures. A large number of real and fictional stories have rings as inanimate protagonists. The design, development or just discovering of a special ring has often been taken as a symbol of power or success. Several examples are the Piscatory Ring wore by the Pope of the Catholic Church, the NBA Championship ring and the One Ring created by the Dark Lord Sauron in the epic story The Lord of the Rings. In this work, we reveal the power of another extremely powerful kind of rings to fight against the pandemic which is currently affecting the whole world. These rings are as small as ~1 nm of diameter and so versatile that they are able to participate in the attack of viruses, and specifically SARS-CoV-2, in a large range of different ways. This includes the encapsulation and transport of specific drugs, as adjuvants to stabilize proteins, vaccines or other molecules involved in the infection, as cholesterol trappers to destabilize the virus envelope, as carriers for RNA therapies, as direct antiviral drugs and even to rescue blood coagulation upon heparin treatment. "One ring to rule them all. One ring to find them. One ring to bring them all and in the darkness bind them." J. R. R. Tolkien.

In Vitro-In Silico Modeling Approach to Rationally Designed Simple and Versatile Drug Delivery Systems.

Rational design and development of a nanosystem usually relies on empirical approaches as well as a fair degree of serendipity. Understanding how nanosystems behave at the molecular level is of great importance for potential biomedical applications. In this work, we describe a nanosystem composed of two natural compounds, vitamin E and sphingomyelin, prepared by spontaneous emulsification (vitamin E-sphingomyelin nanosystems (VSNs)). Extensive characterization revealed suitable physicochemical properties, very high biocompatibility in vitro and in vivo, and colloidal stability during storage and in biological media, all relevant properties for clinical translation. We have additionally pursued a computational approach to gain an improved understanding of the assembling, structure, dynamics, and drug-loading capacity of VSNs, using both small molecules and biomolecules (resveratrol, curcumin, gemcitabine, and two peptides). The spontaneous formation of compartmentalized VSNs starting from completely disassembled molecules, observed here for the first time, was accurately assessed from the computational molecular dynamics trajectories. We describe here a synergistic in silico/in vitro approach showing the predictive power of computational simulations for VSNs' structural characterization and description of internal interaction mechanisms responsible for the association of bioactive molecules, representing a paradigm shift in the rational design of nanotechnologies as drug delivery systems for advanced personalized medicine.

Rings, Hexagons, Hetals, and Dipolar Moment Sink-Sources: The Fanciful Behavior of Water around Cyclodextrin Complexes.

The basket-like geometry of cyclodextrins (CDs), with a cavity able to host hydrophobic groups, makes these molecules well suited for a large number of fundamental and industrial applications. Most of the established CD-based applications rely on trial and error studies, often ignoring key information at the atomic level that could be employed to design new products and to optimize their use. Computational simulations are well suited to fill this gap, especially in the case of CD systems due to their low number of degrees of freedom compared with typical macromolecular systems. Thus, the design and validation of solid and efficient methods to simulate and analyze CD-based systems is key to contribute to this field. The behavior of supramolecular complexes critically depends on the media where they are embedded, so the detailed characterization of the solvent is required to fully understand these systems. In the present work, we use the inclusion complex formed by two α-CDs and one sodium dodecyl sulfate molecule to test eight different parameterizations of the GROMOS and AMBER force fields, including several methods aimed to increase the conformational sampling in computational molecular dynamics simulation trajectories. The system proved to be extremely sensitive to the employed force field, as well as to the presence of a water/air interface. In agreement with previous experiments and in contrast to the results obtained with AMBER, the analysis of the simulations using GROMOS showed a quick adsorption of the complex to the interface as well as an extremely exotic behavior of the water molecules surrounding the structure both in the bulk aqueous solution and at the water surface. The chirality of the CD molecule seems to play an important role in this behavior. All together, these results are expected to be useful to better understand the behavior of CD-based supramolecular complexes such as adsorption or aggregation driving forces, as well as to introduce new methods able to speed up general MD simulations.

Parallel Versus Antiparallel ß-Sheet Structure in Cyclic Peptide Hybrids Containing γ- or δ-Cyclic Amino Acids.

Cyclic peptides with disc-shaped structures have emerged as potent building blocks for the preparation of new biomaterials in fields ranging from biological to material science. In this work, we analyze in depth the self-assembling properties of a new type of cyclic peptides based on the alternation of α-residues and cyclic δ-amino acids (α,δ-CPs). To examine the preferred stacking properties adopted by cyclic peptides bearing this type of amino acids, we carried out a synergistic in vitro/in silico approximation by using simple dimeric models and then extended to nanotubes. Although these new cyclic peptides (α,δ-CPs) can interact either in a parallel or antiparallel fashion, our results confirm that although the parallel ß-sheet is more stable, it can be switched to the antiparallel stacking by choosing residues that can establish favorable cross-strand interactions. Moreover, the subsequent comparison by using the same methodology but applied to α,γ-CPs models, up to the moment assumed as antiparallel-like d,l-α-CPs, led to unforeseen conclusions that put into question preliminary conjectures about these systems. Surprisingly, they tend to adopt a parallel ß-sheet directed by the skeleton interactions. These results imply a change of paradigm with respect to cyclic peptide designs that should be considered for dimers and nanotubes.

Skeletal diversity in Pt- and Au-catalyzed annulations of allenedienes: dissecting unconventional mechanistic pathways.

We describe the discovery of unprecedented annulation processes of 1,7-allenedienes, promoted by Pt or Au catalysts. These transformations revealed mechanistic pathways that had not been previously observed in reactions involving carbophilic catalysis. In particular, we have found that allenedienes bearing a silyl ether in the carbon tether connecting the diene and the allene divergently afford cyclopropane-embedded tricyclic derivatives, 6,6-fused bicarbocyclic products or 5,6-fused bicarbocyclic systems, depending on the type of Au or Pt catalyst used. We have carried out experimental and computational studies that shed light on the mechanistic reasons behind this rich and unusual skeletal divergence, and provide new lessons on the drastic influence of platinum ancillary ligands on the reaction outcome.

Competitive double-switched self-assembled cyclic peptide nanotubes: a dual internal and external control.

"Intelligent" materials based on synthetic small molecules that become functional only under specific conditions provide new opportunities for developing regulated systems aimed at a large number of applications. For instance, biologically active supramolecular entities that are sensitive to environmental conditions, such as the presence of bacterial membranes, are extremely interesting in biomedicine. In this work, we have designed and investigated, using molecular dynamics simulations, a doubly modulable nanotube formed by the self-assembly of cyclic peptides sensitive to both the presence of a lipid membrane and the pH of the aqueous media. The cyclic peptides were designed to self-assemble into peptide nanotubes in the presence of a lipid bilayer and at low pH values. Under these conditions, the residual side chains point outside the cyclic peptides, being exposed to the lipid bilayer, and the inner groups (carboxylic acids) are protonated, thus allowing the permeation of water and preventing that of ions. Higher pH values are expected to create carboxylate groups at the lumen of the peptides, leading to the disassembly of the nanotube, the attraction and translocation of ions towards the hydrophobic core of the bilayer, and eventually killing the target malignant cells. Our results suggest that by introducing a second switch in a membrane sensitive system, it is possible to modulate its interaction with the lipid bilayer. This opens the door to new strategies for the preparation of antimicrobial peptides that interact at the membrane level.

Tight Xenon Confinement in a Crystalline Sandwich-like Hydrogen-Bonded Dimeric Capsule of a Cyclic Peptide.

A cyclic hexapeptide with three pyridyl moieties connected to its backbone forms a hydrogen-bonded dimer, which tightly encapsulates a single xenon atom, like a pearl in its shell. The dimer imprints its shape and symmetry to the captured xenon atom, as demonstrated by 129 Xe NMR spectroscopy, single-crystal X-ray diffraction, and computational studies. The dimers self-assemble hierarchically into tubular structures to form a porous supramolecular architecture, whose cavities are filled by small molecules and gases.

GADDLE Maps: General Algorithm for Discrete Object Deformations Based on Local Exchange Maps.

A new method for switching between structures consisting of equivalent discrete and flexible objects with different particle representation and object configuration, including different resolution levels (number of particles per object), is reported. The method is fully general since it does not require any extra code nor additional database elements for new systems. It is based on a Monte Carlo sampling of the configurational space for each object type of the target system. The sampling is controlled by a Metropolis acceptance criterion of movements (translations, rotations, and relative deformations of the object configuration) that uses the generalized distance between the sets of particles at both representations. For Gaussian distributed distances, such a minimization procedure is equivalent to an optimization of χ2 in a maximum likelihood method. This provides sound statistical support since the method leads to the most probable configuration of the system at each representation. The configurations obtained in this way are then used to create resolution exchange maps for each object type, which allows the extrapolation of the conversion to every object configuration throughout the whole system. As an example, the method is here tested with several molecular dynamics simulated systems (ionic liquids, cyclodextrins, cell-penetrating peptides, cyclic peptides, lipid bilayers, vesicles, heterogeneous organic molecules, DNA, and solvated proteins) for different resolution force fields (GROMOS, AMBER, OPLS, MARTINI) using GROMACS. In this context, the method can be applied to map structures described by any other pair of force fields, as well as to homogeneous and heterogeneous systems with many different molecules. The method is proved to be highly efficient since the time required for the mapping is practically independent of the number of molecules in the target system.