Computational Pharmaceutical Chemistry and Molecular Informatics Group

Permanent URI for this collectionhttps://researchdata.hhu.de/handle/entry/76

Our research focusses on understanding, predicting, and modulating biomolecular interactions from an atomistic perspective.

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Revised data for "Mechanistic Insights into the Structural Asymmetry of the LanFEG Transporter NisFEG in Lantibiotic Immunity"
(2026) Cea, Pablo; Gohlke, Holger
Nisin is one of the best studied antimicrobial peptides. Still, how nisin-producing strains can protect themselves against nisin’s bactericidal effects is only partially understood. Located within the nisin biosynthesis operon, the heterotetrameric ABC transporter NisFEG transports nisin to the extracellular environment, granting autoimmunity to the producer strain. NisFEG belongs to the LanFEG family of ABC transporters, members of which are found in some lantibiotic-producing bacterial strains. However, their structure has not been elucidated. In this work, we constructed a full atom model of NisFEG in the ATP-bound conformation. The architecture of the complex reveals a narrow contact interface between the two transmembrane chains, with prominent lateral clefts, similar to those observed in other exporters of hydrophobic compounds. Through molecular dynamics (MD) simulations, we observed that one of the most conserved elements of the LanFEG family, the E-loop of the nucleotide-binding domain, interacts preferentially with a small intracellular helix of the NisG transmembrane chain. By combining co-solvent MD simulations and predictions of the binding mode of the terminal segment of nisin, we could identify a putative interaction surface, located predominantly on NisE. Our results suggest that nisin extrusion operates in an asymmetric manner, where contacts between the E-loop and NisG are the driving force for the conformational changes triggered by ATP hydrolysis, whereas the NisE subunit is the main mediator of interactions with the lantibiotic. This functional asymmetry could explain why the LanFEG family has evolved two distinct transmembrane chains, where each one was selected to perform a single step in an optimal way, maximizing the immunity of lantibiotic-producing bacteria.
Revised Data for "LignAmb25: A Comprehensive AMBER Force Field Addressing Lignin’s Structural and Chemical Diversity"
(2026) Lapsien, Marco; Bonus, Michele; Greb, Julian; Gohlke, Holger
LignAmb25 is a comprehensive force field for lignin molecular dynamics simulations implemented natively within the AMBER package. The force field includes parameters for all common monolignol units (p-coumaryl, coniferyl, caffeyl, and sinapyl alcohol) and their associated linkages (β O4, β 5, β β, β 1, 5 5, 5 O4, α-O4, BDO, and DBDO), along with less commonly encountered units such as tricin, spirodienones, and hydroxystilbenes. This enables simulations of both softwood and hardwood lignin structures with compositions that would be difficult to isolate experimentally. Force field parameters were initially derived from the GAFF2 force field and systematically optimized using quantum mechanical calculations at the ωB97X D4/def2 TZVPP level of theory on conformer ensembles derived via the CREST/CENSO conformational sampling toolchain. Partial atomic charges were derived using the RESP methodology, consistent with AMBER conventions. Experimentally measured crystal structures of lignin simulated with LignAmb25 accurately retain their packing based on calculations of the RMSD and density error compared to the deposited crystal structure, thereby exceeding the performance of the lignin force field for CHARMM. Additionally, LignAmb25 is shown to reliably estimate the enthalpy of vaporization and the absolute hydration free energy of lignin-related compounds. The LignAmb25 force field is provided in two variants: LignAmb25Solo, a standalone version not meant for use with other biomolecular force fields that focuses on accurate modelling of lignin solvent interactions, and LignAmb25HF, a version that is compatible with all other major biomolecular force fields in the AMBER molecular dynamics suite. This includes force fields of the GLYCAM (carbohydrates), ff19SB (proteins), and LIPID (lipids) families, as well as the DNA and RNA force fields routinely used in AMBER. The LignAmb25 force field will be distributed as of AMBER 26.
Overcoming bottlenecks for microbial production of the low-caloric sweetener D-allulose from D-glucose by evolutionary engineering
(2026) Gentile, Rocco; Gohlke, Holger
The low-calorie sugar D-allulose is a promising alternative to D-sucrose and high-fructose corn syrup, but its microbial production from D-glucose at mesophilic temperatures is limited by insufficient D-glucose isomerase (XylA) activity. Here, we overcome this bottleneck by evolving a Corynebacterium glutamicum selection strain whose growth strictly depends on XylA function. This strategy yielded a XylA variant with a nine-fold higher catalytic efficiency, sugar transporter variants (IolT1) with ten-fold increased activity for D-glucose and D-fructose, and hints for co-transport of these sugars by the D-sucrose transporter PtsS. Molecular dynamics simulations provided mechanistic explanations for the adaptive mutations. Combining the evolved enzymes with a suitable D-allulose 3-epimerase in a highly engineered chassis strain enabled whole-cell conversion of D-glucose to D-allulose with a 15% yield at 30 °C. This performance rivals high-temperature immobilized enzyme processes while avoiding enzyme purification and immobilization, offering an alternative for low-calorie sweetener production.
Data for "LignAmb25: A Comprehensive AMBER Force Field Addressing Lignin’s Structural and Chemical Diversity"
(2026) Lapsien, Marco; Bonus, Michele; Greb, Julian; Gohlke, Holger
LignAmb25 is a comprehensive force field for lignin molecular dynamics simulations implemented natively within the AMBER package. The force field includes parameters for all common monolignol units (p-coumaryl, coniferyl, caffeyl, and sinapyl alcohol) and their associated linkages (β O4, β 5, β β, β 1, 5 5, 5 O4, α-O4, BDO, and DBDO), along with less commonly encountered units such as tricin, spirodienones, and hydroxystilbenes. This enables simulations of both softwood and hardwood lignin structures with compositions that would be difficult to isolate experimentally. Force field parameters were initially derived from the GAFF2 force field and systematically optimized using quantum mechanical calculations at the ωB97X D4/def2 TZVPP level of theory on conformer ensembles derived via the CREST/CENSO conformational sampling toolchain. Partial atomic charges were derived using the RESP methodology, consistent with AMBER conventions. Experimentally measured crystal structures of lignin simulated with LignAmb25 accurately retain their packing based on calculations of the RMSD and density error compared to the deposited crystal structure, thereby exceeding the performance of the lignin force field for CHARMM. Additionally, LignAmb25 is shown to reliably estimate the enthalpy of vaporization and the absolute hydration free energy of lignin-related compounds. The LignAmb25 force field is provided in two variants: LignAmb25Solo, a standalone version not meant for use with other biomolecular force fields that focuses on accurate modelling of lignin solvent interactions, and LignAmb25HF, a version that is compatible with all other major biomolecular force fields in the AMBER molecular dynamics suite. This includes force fields of the GLYCAM (carbohydrates), ff19SB (proteins), and LIPID (lipids) families, as well as the DNA and RNA force fields routinely used in AMBER. The LignAmb25 force field will be distributed as of AMBER 26.
Data for "Mechanistic Insights into the Structural Asymmetry of the LanFEG Transporter NisFEG in Lantibiotic Immunity"
(2025) Cea, Pablo; Gohlke, Holger
Nisin is one of the best studied antimicrobial peptides. Still, how nisin-producing strains can protect themselves against nisin’s bactericidal effects is only partially understood. Located within the nisin biosynthesis operon, the heterotetrameric ABC transporter NisFEG transports nisin to the extracellular environment, granting autoimmunity to the producer strain. NisFEG belongs to the LanFEG family of ABC transporters, members of which are found in some lantibiotic-producing bacterial strains. However, their structure has not been elucidated. In this work, we constructed a full atom model of NisFEG in the ATP-bound conformation. The architecture of the complex reveals a narrow transmembrane interface with prominent lateral clefts, similar to those observed in other exporters of hydrophobic compounds. Through molecular dynamics (MD) simulations, we observed that one of the most conserved elements of the LanFEG family, the E-loop of the nucleotide binding domain, interacts preferentially with a small intracellular helix of the NisG transmembrane chain. Cosolvent MD simulations reveal the presence of a putative binding site within the lateral cleft of the transporter, next to the transmembrane chain NisE. Mutational analysis showed that large hydrophobic residues near this putative site are relevant to the transporter function, and more so than analogous residues in the opposite cleft. Our results suggest that nisin extrusion operates in an asymmetric manner, where contacts between the E-loop and NisG are the driving force for the conformational changes triggered by ATP hydrolysis, whereas the NisE subunit is the main mediator of interactions with the lantibiotic. This functional asymmetry could provide an explanation for why the LanFEG family has evolved two distinct transmembrane chains, where each one was selected to perform a single step in an optimal way, maximizing the immunity of lantibiotic-producing bacteria.
Data for "Early-stage autophagy inhibitors targeting the ATG101-ATG13 subunit of the ULK1 complex"
(2025) Mudrovcic, Korana; Gopalswamy, Mohanraj; Gohlke, Holger
Autophagy is commonly up- or down-regulated in cancer cells due to the unique metabolic needs of these cells, and small molecules modulating the autophagy pathway are already in clinical trials. However, specific autophagy-targeting compounds remain rare. A new potential mechanism for effective early-stage autophagy inhibition was described by us and others recently, involving the inhibition of the interaction between ATG101 and ATG13 subunits of the autophagy-initiating ULK1 complex. Here, we describe the discovery of two small molecules inhibiting the ATG101-ATG13 interaction, one by binding to ATG101 with micromolar affinity (EC50 = 151 µM) and the other by binding to both ATG101 and ATG13 with micromolar affinity (EC50 = 135 µM and EC50 = 107 µM, respectively). In two independent assays, both compounds inhibit autophagy. Scrutinizing the binding mechanism by molecular dynamics simulations and STD-NMR spectroscopy indicates that the compounds bind to ATG101 in an orthosteric fashion, at the interface of the protein-protein interaction, while the binding to ATG13 is allosteric. Both compounds have a favorable predicted ADME-Tox profile. The compounds can serve as tool compounds to inhibit autophagy or as candidates for further optimization toward lead structures.
Data for "Identification of autophagy inhibitors selectively targeting the ATG13-ATG101 protein-protein interaction"
(2025) Mudrovcic, Korana; Gopalswamy, Mohanraj; Gohlke, Holger
The dysregulation of autophagy promotes the development of several diseases like such as neurodegeneration, infection, or cancer. To keep up with their metabolic demand under low nutrient and/or oxygen conditions typically present in the tumor microenvironment, cancer cells can upregulate autophagy autonomously or in surrounding cells. Therefore, the inhibition of autophagy is desired in these settings. However, to date, drugs targeting autophagy selectively remain rare. The autophagy-inducing ULK1 complex comprises ULK1/2, FIP200, and a heterodimer consisting of ATG13 and ATG101. We previously showed that the ATG13-ATG101 protein-protein interaction is crucial for the assembly of the ULK1 complex and initiation of autophagic activity. Thus, targeting the ATG13-ATG101 protein-protein interaction with small molecules promises to yield new tools for the study of autophagy as well as to deliver new therapeutic starting points. By screening a diversity set of 15k compounds in a biochemical setup, followed by extensive cell-based validation studies, we identified the compounds AFS30 and AFS32. Both compounds inhibited the ATG13-ATG101 PPI in the low micromolar range and led to reduced autophagic activity in different cell lines, with IC50 values of 3-4 µM in the LC3 HiBiT reporter assay. Spectral shift assays, molecular dynamics simulations, and STD-NMR suggested that the compounds bind allosterically to ATG13. AFS30 and AFS32 also promoted apoptosis in different cancer cell lines exposed to nutrient stress. We propose that AFS30 and AFS32 are promising lead compounds for the development of PPI inhibitors that selectively inhibiting the ATG13-ATG101 interaction and thus autophagy.
Data for "Sulfated glycosaminoglycans inhibit LCMV entry and modulate antiviral immunity and pathology"
(N/A, 2025) Rähse, Nick; Lapsien, Marco; Gohlke, Holger
Viral infections pose significant challenge due to limited availability and efficacy of treatments. Current therapies primarily inhibit viral replication, but are often virus-specific and may lead to drug resistance. Sulfated glycosaminoglycans (GAGs) emerged as promising candidates for antiviral therapy, preventing viral binding to host cells and inhibiting cell entry, offering a novel therapeutic strategy targeting broad range of viruses, addressing the limitations of existing antiviral drugs. Here, we demonstrate highly-sulfated GAGs are able to limit infectivity of different pathogenic and non-pathogenic Arenaviruses. In an in vivo model setting, dextran sulfate administered during the acute phase of LCMV infection reduced viral load in organs and decreased liver pathology, which was associated with improved effector T cell functions. In turn, exposure of LCMV towards dextran sulfate at the beginning of infection caused limited immune activation, resulting in reduced T cell immunity, prolonged infection and increased immunopathology. These findings indicate the potential use of GAGs against Arenavirus infections and highlight that timing of therapeutic regimens might be critical for clinical efficacy.
Data for "Evidence for Epibatidine Binding to the Desensitization Gate in α7 nAChR from Molecular Dynamics Simulations and Cryo-EM"
(N/A, 2025) Kaiser, Jesko; Gertzen, Christoph; Mann, Daniel; Sachse, Carsten; Gohlke, Holger
The homopentameric α7 nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel widely expressed in the human nervous system and susceptible to regulation via allosteric modulators. A recent cryo-EM map of the receptor (EMD 22983) in the presence of (±)-epibatidine revealed the presence of several Coulomb density regions that did not contain an atomic model (PDB ID: 7KOX). We conducted unbiased molecular dynamics simulations of free ligand diffusion of the components of experimental buffers utilized to obtain the cryo-EM structure in the presence of α7-nAChR. In addition to the previously documented binding of epibatidine to the orthosteric site and Ca2+ between E44 and E172, the simulations indicated that epibatidine can also bind within the pore of α7-nAChR. This finding is consistent with the unmodeled Coulomb density observed in the region of the desensitization gate. The data presented here suggests that nAChR ligands characterized as orthosteric binders may bind to additional sites within the receptor and expands the receptor’s pocketome.
Data for "Molecular Insights into CLD Domain Dynamics and Toxin Recruitment of the HlyA E. coli T1SS"
(N/A, 2025) Gentile, Rocco; Schott-Verdugo, Stephan; Khosa, Sakshi; Bonus, Michele; Reiners, Jens; Smits, Sander H.J.; Schmitt, Lutz; Gohlke, Holger
Escherichia coli is a Gram-negative opportunistic pathogen causing nosocomial infections through the production of various virulence factors. Type 1 secretion systems (T1SS) contribute to virulence by mediating one-step secretion of unfolded substrates directly into the extracellular space, bypassing the periplasm. A well-studied example is the hemolysin A (HlyA) system, which secretes the HlyA toxin in an unfolded state across the inner and outer membranes. T1SS typically comprise a homodimeric ABC transporter (HlyB), a membrane fusion protein (HlyD), and the outer membrane protein TolC. Some ABC transporters in T1SS also contain N-terminal C39 peptidase or peptidase-like (CLD) domains implicated in substrate interaction. Recent cryo-EM studies have resolved the inner-membrane complex as a trimer of HlyB homodimers with associated HlyD protomers. However, a full structural model including TolC remains unavailable. We present the first complete structural model of the HlyA T1SS, constructed using template- and MSA-based information and validated by SAXS. Molecular dynamics simulations provide insights into the function of the CLD domains, which are partially absent from existing cryo-EM structures. These domains may modulate transport by stabilizing specific conformations of the complex. Simulations with a C-terminal fragment of HlyA indicate that toxin binding occurs in the occluded conformation of HlyB, potentially initiating substrate transport through a single HlyB protomer before transitioning to an inward-facing state. HlyA binding also induces allosteric effects on HlyD, altering key residues involved in TolC recruitment. These results indicate how substrate recognition and transport are coupled and may support the development of antimicrobial strategies targeting the T1SS.
Data for "Influence of ionic liquids on enzymatic asymmetric carboligations"
(N/A, 2025) El Harrar, Till; Gohlke, Holger
The asymmetric mixed carboligation of aldehydes catalyzed by thiamine diphosphate (ThDP)-dependent enzymes provides a sensitive system for monitoring changes in activity, chemo-, and enantioselectivity. While previous studies have shown that organic cosolvents influence these parameters, we now demonstrate that similar effects occur upon addition of water-miscible ionic liquids (ILs). In this study, six ThDP-dependent enzymes were analyzed in the presence of 14 ILs under comparable conditions to assess their influence on enzymatic carboligation reactions yielding 2-hydroxy ketones. ILs exerted a moderate to strong influence on activity and, more notably, altered enantioselectivity. (R)-selective reactions were generally stable upon IL addition, while (S)-selective reactions frequently showed reduced selectivity or even inversion to the (R)-enantiomer. The most significant change was observed for the ApPDC_E469G variant of pyruvate decarboxylase from Acetobacter pasteurianus, where the enantiomeric excess shifted from 86% (S) to 60% (R) in the presence of 9% (w/v) Ammoeng 102. Control experiments indicated that this shift was primarily due to the Ammoeng cation rather than the anion. To explore the molecular basis of this phenomenon, all-atom molecular dynamics (MD) simulations were performed on wild-type ApPDC and the E469G variant in Ammoeng 101 and Ammoeng 102. The simulations revealed that hydrophobic and hydrophilic regions of the Ammoeng cations interact with the (S)-selective binding pocket, thereby favoring formation of the (R)-product. These results highlight the potential of solvent engineering for modulating enzyme selectivity and demonstrate that MD simulations can capture functionally relevant enzyme–solvent interactions at the atomic level.
Chaperone/ETR1 Structural Models for: Molecular Mechanism and Structural Models of Protein-Mediated Copper Transfer to the Arabidopsis thaliana Ethylene Receptor ETR1 at the ER Membrane
(N/A, 2025) Dluhosch, Dominik; Kersten, Lisa Sophie; Minges, Alexander; Schott-Verdugo, Stephan; Gohlke, Holger; Groth, Georg
In plants, the gaseous plant hormone ethylene regulates a wide range of developmental processes and stress responses. The small unsaturated hydrocarbon is detected by a family of receptors (ETRs) located in the membrane of the endoplasmic reticulum, which rely on a monovalent copper cofactor to detect this hydrocarbon. The copper-transporting P-type ATPase RAN1 (HMA7), located in the same membrane, is known to be essential for the biogenesis of ETRs. Still, the precise molecular mechanism by which the receptors acquire their copper cofactor remains unclear. A recent study by our laboratory demonstrated a direct interaction between RAN1 and soluble copper chaperones of the ATX1 family with the model ethylene receptor ETR1, providing initial insights into the mechanism by which copper is transferred from the cytosol to the membrane-bound receptors. In this study, we further investigated these interactions with respect to the function of individual domains in complex formation. To this end, we combined biochemical experiments and computational predictions and unraveled the processes and mechanisms by which copper is transferred to ETR1 at the molecular level.
SQLite file for TopCysteineDB: A Cysteinome-wide Database Integrating Structural and Chemoproteomics Data for Cysteine Ligandability Prediction
(N/A, 2025-04) Bonus, Michele; Greb, Julian; Majmudar, Jaimeen D.; Boehm, Markus; Korczynska, Magdalena; Nazemi, Azadeh; Mathiowetz, Alan M.; Gohlke, Holger
Development of targeted covalent inhibitors and covalent ligand-first approaches have emerged as a powerful strategy in drug design, with cysteines being attractive targets due to their nucleophilicity and relative scarcity. While structural biology and chemoproteomics approaches have generated extensive data on cysteine ligandability, these complementary data types remain largely disconnected. Here, we present TopCysteineDB, a comprehensive resource integrating structural information from the PDB with chemoproteomics data from activity-based protein profiling experiments. Analysis of the complete PDB yielded 264,234 unique cysteines, while the proteomics dataset encompasses 41,898 detectable cysteines across the human proteome. Using TopCovPDB, an automated classification pipeline complemented by manual curation, we identified 787 covalent cysteines and systematically categorized other functional roles, including metal-binding, cofactor-binding, and disulfide bonds. Mapping residue-wise structural information to sequence space enabled cross-referencing between structural and proteomics data, creating a unified view of cysteine ligandability. For TopCySPAL, a machine learning model was developed, integrating structural features and proteomics data, achieving strong predictive performance (AUROC: 0.964, AUPRC: 0.914) and robust generalization to novel cases. TopCysteineDB and TopCySPAL are freely accessible through a webinterface, TopCysteineDBApp (https://topcysteinedb.hhu.de/), designed to facilitate exploration of cysteine sites across the human proteome. The interface provides an interactive visualization featuring a color-coded mapping of chemoproteomics data onto cysteine site structures and the highlighting of identified peptide sequences. It offers customizable dataset downloads and ligandability predictions for user-provided structures. This resource advances targeted covalent inhibitor design by providing integrated access to previously dispersed data types and enabling systematic analysis and prediction of cysteine ligandability.
Data for "TopEC: Improved classification of enzyme function by a localized 3D protein descriptor and 3D Graph Neural Networks"
(N/A, 2024-08-25) van der Weg, Karel; Merdivan, Erinc; Piraud, Marie; Gohlke, Holger
Accurately annotating molecular function of enzymes remains challenging. Computational methods can aid in this and allow for high-throughput annotation. Tools available for inferring enzyme function from general sequence, fold, or evolutionary information are generally successful. However, they can lead to misclassification if for certain sequences a deviation in local structural features influences the function. Here, we present TopEC, a 3D graph neural network based on a localized 3D descriptor to learn chemical reactions of enzymes from (predicted) enzyme structures and predict Enzyme Commission (EC) classes. Using the message passing frameworks from SchNet and DimeNet++, we include distance and angle information to improve the predictive performance compared to regular 2D graph neural networks. We obtained significantly improved EC classification prediction (F-score: 0.72) to 2D GNNs, without fold bias at residue and atomic resolutions and trained networks that can classify both experimental and computationally generated enzyme structures for a vast functional space (> 800 ECs). Our model is robust to uncertainties in binding site locations and similar functions in distinct binding sites. By investigating the importance of each graph node to the predictive performance, we see that TopEC networks learn from an interplay between biochemical features and local shape-dependent features. TopEC is available as a repository, including accompanying data, on github: https://github.com/IBG4-CBCLab/TopEC. The data in this repository is available under the CC-BY-NC-SA 4.0 license.
Supporting Information for "Molecular mechanisms underlying single nucleotide polymorphism-induced reactivity decrease in CYP2D6"
(N/A, 2024-02) Becker, Daniel; Gohlke, Holger
Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes involved in drug metabolism. Genetic polymorphism can influence drug metabolism by CYP2D6 such that a therapy is seriously affected by under- or overdosing of drugs. However, a general explanation at the atomistic level for poor activity is missing so far. Here we show for the 20 most common single nucleotide polymorphisms (SNPs) of CYP2D6 that poor metabolism is driven by four mechanisms. We found in extensive all-atom molecular dynamics simulations that the rigidity of the I-helix (central helix), distance between central phenylalanines (stabilizing bound substrate), availability of basic residues on the surface of CYP2D6 (binding of Cytochrome P450 reductase), and position of arginine 132 (electron transfer to heme) are essential for an extensive function of the enzyme. These results were applied to SNPs with unknown effects and potential SNPs that may lead to poor drug metabolism were identified. The revealed molecular mechanisms might be important for other drug-metabolizing Cytochrome P450 enzymes.
MD simulation data for: "Molecular Mechanisms Underlying Medium-Chain Free Fatty Acid-regulated Activity of the Phospholipase PlaF from Pseudomonas aeruginosa"
(N/A, 2023-11) Gentile, Rocco; Schott-Verdugo, Stephan; Gohlke, Holger
PlaF is a membrane-bound phospholipase A1 from P. aeruginosa that is involved in remodeling membrane glycerophospholipids (GPLs) and modulation of virulence-associated signaling and metabolic pathways. Previously, we identified the role of medium-chain free fatty acids (FFA) in inhibiting PlaF activity and promoting homodimerization, yet the underlying molecular mechanism remained elusive. Here, we used unbiased and biased molecular dynamics simulations and free energy computations to assess how PlaF interacts with FFAs localized in the water milieu surrounding the bilayer or within the bilayer, and how these interactions regulate PlaF activity. Medium-chain FFAs localized in the upper bilayer leaflet can stabilize inactive dimeric PlaF, likely through interactions with charged surface residues as experimentally validated. Potential of mean force (PMF) computations indicate that membrane-bound FFAs may facilitate the activation of monomeric PlaF by lowering the activation barrier of changing into a tilted, active configuration. We estimated that the coupled equilibria of PlaF monomerization-dimerization and tilting at the physiological concentration of PlaF lead to the majority of PlaF forming inactive dimers when in a cell membrane loaded with decanoic acid (C10). This is in agreement with a suggested in vivo product feedback loop and GC-MS profiling results indicating that PlaF catalyzes the release of C10 from P. aeruginosa membranes. Additionally, we found that C10 in the water milieu can access the catalytic site of active monomeric PlaF, contributing to the competitive component of C10-mediated PlaF inhibition. Our study provides mechanistic insights into how medium-chain FFA may regulate the activity of PlaF, a potential bacterial drug target.
MD simulation data for: "The cyclophilin A binding loop of the capsid regulates the human TRIM5α sensitivity of nonpandemic HIV-1"
(N/A, 2023-11) Becker, Daniel; Münk, Carsten; Gohlke, Holger
All MD input structures, MD infiles, umbrella sampling files, and scripts that were used to analyze the umbrella sampling results are provided in this supporting repository.
Regulation of STING activity in DNA sensing by ISG15 modification
(N/A, 2023-09) Gertzen, Christoph; Kaiser, Jesko; Münk, Carsten; Gohlke, Holger
Molecular modeling and simulations suggest that ISGylation of K289 of STING is an important regulator of STING oligomerization
Supporting Information for "Enzyme adaptation to habitat thermal legacy shapes the thermal plasticity of marine microbiomes"
(N/A, 2023-01) Nutschel, Christina; Pfleger, Christopher; Dittrich, Jonas; Gohlke, Holger
The dataset contains: I. 3D structural models of esterases generated by a AlphaFold2-based workflow of ColabFold, II. predicted catalytic triads of esterases and their substrate accessibilities analyzed by CAVER 3.0.3 PyMOL Plugin, III. input and output files for molecular dynamics (MD) simulations performed by Amber21, and, IV. Tp-values of esterases predicted by Constraint Network Analysis (CNA). We added template scripts and a readme file for further explanations.
Supporting Information for "Loading and Co-Solvent-Triggered Release of Okanin, a C4 Plant Key Enzyme Inhibitor, into/from Functional Microgels"
(N/A, 2023-01) Dittrich, Jonas; Gohlke, Holger
The constantly growing world population leads to increasing demands for food, which challenges modern agriculture manifold. Pests, such as weeds, require the application of agrochemicals to increase crop yield. Due to the environmental impact of these potentially hazardous chemicals, the demand for more efficient formulations is increasing. Promising formulations consist of easily adaptable carriers from which controllable stimuli release the agrochemicals. Here, we investigated poly(N vinylcaprolactam) (pVCL)-based microgels as a potential carrier for okanin, an inhibitor of the C4 plant key enzyme phosphoenolpyruvate carboxylase, by combining experiments, molecular simulations, and free energy computations. Dynamic light scattering, scanning transmission electron and atomic force microscopy revealed that pVCL microgels collapse and rigidify upon the loading of okanin. The simulations identified loosely adsorbed okanin and tightly bound okanin mediating inter-chain crosslinks. With increasing okanin concentration, stacking interactions of okanin occur with adsorbed and bound okanin. These findings can explain the experimentally observed collapse and the rigidification of the microgels. Based on the atomistic insights, two poly(N vinylcaprolactam co glycidyl methacrylate) microgels were synthesized, for which a doubled loading capacity of okanin was found. Finally, we investigated the triggered release of okanin using the addition of green solvents as a stimulus. This work establishes a basis for the further optimization of pVCL-based microgels as a carrier for the delivery of polyphenolic agrochemicals.

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