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Ligand-Conjugates Targeting an Intracellular Allosteric Site for Neurotensin Receptor-1
Get PDFNeurotensin receptor-1 (NTSR1) plays a crucial role in cellular signaling and has been implicated in various diseases, including cancer and neurological disorders. This thesis explores innovative strategies for targeting NTSR1 through the design of specialized ligands and conjugates. Key efforts include the development of bivalent ligands to investigate receptor interactions, fluorescent probes for advanced ligand screening, and therapeutic conjugates designed to exploit receptor-specific mechanisms. These approaches aim to enhance our understanding of NTSR1 function and provide novel tools for its potential therapeutic targeting. The findings contribute to broader efforts in drug discovery and receptor biology
Ab initio Untersuchung zur Auswirkung von struktuellen Motiven auf die Bruchfestigkeit von Silizium
No full textIn the 1920s, Griffith introduced his continuum approach for fracture. Since then, great efforts have been made to describe crack propagation more precisely within continuum mechanics. Nevertheless, it is evident that the atomic structure of the crack tip itself plays a crucial role in crack advancement, thus making it necessary to extend the concept of Griffith to the discrete atomic level. This enables the possibility to investigate essential and material specific processes, such as local bond rearrangements and path-dependent activation barriers. In general, crack opening is a complex chemical process on a multi-dimensional potential energy surface with many local minima and saddle points. The complexity increases even further when parameters such as temperature, pressure, or chemical environments are included.
In this study, we discuss first density-functional theory geometry optimizations for crack tips in silicon to investigate brittle fracture mechanics. Our results demonstrate that cracks can propagate through a multitude of local energy minimum configurations connected by a variety of energy barriers. We highlight the complex nature of crack advancement and the challenge of modeling and identifying the correct fracture pathway, even for a material with a simple crystal structure like silicon. One advantage of using silicon is that it is well-described in literature. It is purely brittle, and extensive data on its fracture properties from experiments and simulations is available. The lattice parameters, bulk elastic constants, and surface energies of the relaxed surfaces were determined using calculations done in the generalized-gradient approximation with the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional, using a plane wave basis set, Vanderbilt ultrasoft pseudopotentials, and the semi-empirical Grimme D3 dispersion correction for including van der Waals forces. This data is needed to determine the analytical solution of the long-range atomic displacement field around the crack tip, which is used to displace the atomic lattice accordingly. The finite cutouts from the displaced atomic lattice are referred to as "pacman" structures. The boundaries are saturated with hydrogen atoms, outer atoms are fixed, and the inner part, including the crack surfaces, are relaxed. Thus, the displacement field serves as a boundary condition for the ab initio calculations.
In order to increase the external load, two different approaches are tested. The first approach involves taking cutouts of the pacman structures at different loads, or rather at different stress intensity factors K, and relaxing them individually. The second approach starts at a certain relaxed pacman structure and re-scales the atomic positions linearly in consecutive steps with increasing or decreasing load, with each re-scaling step involving a geometry optimization. As fracture criterion, the length of the first bond closest to the crack tip is chosen. Both approaches lead to different critical loads for fracture. The re-scaling approach, in particular, shows significantly higher critical K-values, since structures are often trapped in stable local energy minima with disadvantageous dimer transition states.
The initial calculations indicate a complex potential energy surface with several possible transition minima for crack propagation. Thus, extensive attention is given to the different possible crack tip relaxations and resulting structures of the crack tip. Furthermore, a strong relation between the surface relaxation and the formed crack tip structure is observed. After probing for different local minima and crack shapes, the focus was shifted to determining possible activation barriers for crack propagation. According to statistical mechanics and for subcritical loads, the reaction path should follow the lowest energy minima. The change in energy is defined relative to the non-relaxed pacman structure and is referred to as center energy. Unfortunately, the center energies of the different crack tip structures are not size independent and exhibit deviating relative energies and system size behavior. This size inconsistency is caused by the mismatch between the originally chosen "mathematical" center of the displacement field and the true "physical" crack tip center after structure optimization. In other words, the structure optimization was carried out with incorrect boundary conditions that correspond to the fixed outer atoms of the cutout, as they were derived from a pacman structure with a wrong displacement field center. Thus, the boundary conditions have to be adjusted until the true physical displacement field aligns with the analytical one for the far-field region where linear elasticity theory applies.
This is illustrated with a thorough analysis of the change in displacements caused by the relaxation of the initial pacman structure. The results of the study show that by shifting the initial displacement field position of the analytical solution within the finite cutout, a significant improvement for the transition to the far-field solution can be observed. The mean mismatch of the displacement field can be plotted against the displacement field center position, which shows a parabolic relation with the minimum at the position where the erroneous contributions from the boundary become minimal. To correct the outer boundary, an iterative correction scheme was implemented. This scheme performs a least square fit between the displacement fields of the relaxed structure and non-relaxed pacman structures with arbitrary displacement field centers. With the new boundary conditions from the selected pacman, the next relaxation calculation is performed. This process is repeated until no better match is found.
This flexible boundary regime has the advantage that the position of the displacement field within the finite cutout can be used as a direct criterion for crack propagation. This suggests that both the boundary conditions and the geometry of the crack tip play a crucial role in determining the activation barrier for crack propagation. By taking into account the effects of boundary conditions and crack tip geometry, it is possible to predict the critical loads for fracture and understand the underlying mechanisms of crack propagation more accurately. Overall, the flexible boundary regime provides a powerful tool for studying fracture in complex materials and structures, and has the potential to improve our understanding of the fundamental processes underlying fracture in brittle materials.In den 1920er Jahren stellte Griffith seinen Kontinuumsansatz für Brüche vor. Seitdem wurden große Anstrengungen unternommen, um die Rissausbreitung innerhalb der Kontinuumsmechanik genauer zu beschreiben. Es ist jedoch offensichtlich, dass die atomare Struktur der Rissspitze selbst eine entscheidende Rolle bei der Rissausbreitung spielt. Daher ist es notwendig, das Konzept von Griffith auf die diskrete atomare Ebene zu erweitern. Dadurch besteht die Möglichkeit, wesentliche materialspezifische Prozesse wie lokale Bindungsumlagerungen und pfadabhängige Aktivierungsbarrieren zu untersuchen. Im Allgemeinen ist die Rissöffnung ein komplexer chemischer Prozess auf einer mehrdimensionalen potentiellen Energieoberfläche mit vielen lokalen Minima und Sattelpunkten. Die Komplexität nimmt noch zu, wenn Parameter wie Temperatur, Druck oder chemische Umgebungen einbezogen werden.
In diesem Zusammenhang diskutieren wir erste Dichtefunktional-basierte Geometrieoptimierungen für Rissspitzen in Silizium um die Sprödbruchmechanik zu untersuchen.
Wir zeigen in unserer Arbeit, dass sich Risse über eine Vielzahl lokaler Energieminima-Konfigurationen ausbreiten können, die über verschiedene Energiebarrieren miteinander verbunden sind. Dabei gehen wir insbesondere auf die komplexe Natur der Rissausbreitung und die Schwierigkeit bei der Modellierung ein, sowie auf das Auffinden des korrekten Bruchweges, selbst für ein Material mit einer so einfachen Kristallstruktur wie Silizium.
Silizium eignet sich besonders für unsere Untersuchungen, da es in der Literatur gut beschrieben ist. Es verhält sich rein spröde und es sind umfangreiche Daten über seine Brucheigenschaften aus Experimenten und Simulationen verfügbar. Wir haben die Gitterparameter, elastischen Konstanten und Oberflächenenergien der relaxierten Oberflächen bestimmt. Diese Berechnungen wurden in Generalized-Gradient-Annäherung mit dem Perdew-Burke-Ernzerhof (PBE)-Austauschkorrelationsfunktional durchgeführt unter Verwendung eines Basissatzes aus ebenen Wellen, ultrasoften Vanderbilt-Pseudopotentialen und der semi-empirischen Grimme-D3-Dispersionskorrektur zur Berücksichtigung von van der Waals-Kräften.
Diese Daten werden benötigt, um die analytische Lösung des langreichweitigen atomaren Verschiebungsfeldes um die Rissspitze zu bestimmen, die das Atomgitter entsprechend verschiebt. Die endlichen Ausschnitte aus dem verschobenen Atomgitter werden als "Pacman"-Strukturen bezeichnet. Die äußeren Si-Atome sind mit Wasserstoffatomen gesättigt und fixiert und der innere Teil, einschließlich der Rissflächen, wird relaxiert.
Das Verschiebungsfeld wird als Randbedingung für die ab-initio-Rechnungen verwendet.
Es wurden zwei verschiedene Ansätze getestet um die externe Zugkraft zu erhöhen. Der erste Ansatz verwendet Ausschnitte der Pacman-Strukturen bei verschiedenen Zuglasten bzw. verschiedenen Spannungsintensitätsfaktoren K und lässt diese einzeln relaxieren. Der zweite Ansatz geht von einer bestimmten relaxierten Pacman-Struktur aus und skaliert linear die Atompositionen in aufeinanderfolgenden Schritten in denen die Zuglast erhöht oder verkleinert wird. Jeder Skalierungsschritt beinhaltet eine Geometrieoptimierung. Als Bruchkriterium wird die Länge der ersten Bindung gewählt, die der Rissspitze am nächsten liegt. Beide Ansätze führen zu unterschiedlichen kritischen Lasten für den Bruch. Insbesondere der Reskalierungsansatz zeigt deutlich höhere kritische K-Werte, da Strukturen oft in stabilen lokalen Energieminima mit ungünstigen Dimerübergangszuständen gefangen sind.
Erste Berechnungen zeigen eine komplexe potentielle Energieoberfläche mit vielen möglichen Übergangsminima für die Rissausbreitung. Dabei wird den verschiedenen möglichen Rissspitzenrelaxationen und den daraus resultierenden Strukturen der Rissspitze besonders große Aufmerksamkeit geschenkt. Es wurde beobachtet, dass die Oberflächenrelaxierung einen starken Einfluss auf die Struktur der gebildeten Rissspitze hat. Nach der Untersuchung verschiedener lokaler Minima und Risskonfigurationen wurde der Fokus darauf gelegt, mögliche Aktivierungsbarrieren für die Rissausbreitung zu bestimmen. Gemäß der statistischen Mechanik sollte bei unterkritischen Belastungen der Reaktionsweg entlang der niedrigsten Energieminima erfolgen. Die Energieänderung ist dabei relativ zur nicht relaxierten Pacman-Struktur definiert und als Zentrumsenergie bezeichnet. Allerdings sind die Zentrumsenergien der verschiedenen Rissspitzenstrukturen nicht unabhängig von der Größe des gewälten Pacman-Ausschnitts und zeigen unterschiedliche relative Energien und Systemverhalten. Dies liegt daran, dass das ursprünglich gewählte "mathematische" Zentrum des Verschiebungsfeldes von dem tatsächlichen "physikalischen" Rissspitzenzentrum nach der Geometrieoptimierung abweicht. Das bedeutet, dass die Geometrieoptimierung mit falschen Randbedingungen durchgeführt wurde, die den festgehaltenen äußeren Atomen während der Rechnung entsprechen, da sie von einer Pacman-Struktur mit einem abweichenden Verschiebungsfeld abgeleitet wurden. Daher müssen die Randbedingungen angepasst werden, bis das tatsächliche physikalische Verschiebungsfeld mit dem analytischen des Fernfeldes, in welchen lineare Elastizität vorausgesetzt werden kann, übereinstimmt.
Dies wird veranschaulicht, indem eine gründlichen Analyse der durch die Relaxation verursachten Änderungen an den anfänglichen Pacman-Strukturen und den damit einhergehenden Änderungen des ursprünglichen Verschiebungsfeldes durchgeführt wird. Eine deutliche Verbesserung des Übergangs zur Fernfeldlösung wird durch eine Anpassung des Ursprunges des anfänglichen Verschiebungsfeldes der analytischen Lösung innerhalb des endlichen Ausschnittes beobachtet. Die akkumulative Änderung der Verschiebungen kann gegen die Position des Ursprungs des Verschiebungsfeldes aufgetragen werden. Es zeigt sich eine parabolische Beziehung mit einem Minimum an der Stelle, an der die fehlerhaften Beiträge minimal werden. Es wurde ein iteratives Korrekturschema implementiert, das die äußeren Randbedingungen korrigiert, indem die minimalen Fehlerquadrate zwischen den Verschiebungsfeldern der relaxierten Struktur und den nicht relaxierten Pacman-Strukturen mit beliebigen Verschiebungsfeldzentren bestimmt werden. Mit den neuen Randbedingungen der ausgewählten Pacman-Struktur wird die nächste Relaxationsberechnung durchgeführt. Dies wird so lange wiederholt, bis keine bessere Übereinstimmung mehr gefunden wird.
Diese flexible Randbedingung hat außerdem den Vorteil, dass die Position des Verschiebungsfeldes innerhalb des endlichen Ausschnitts als direktes Kriterium für die Rissausbreitung verwendet werden kann. Dies legt nahe, dass sowohl der Randbereich als auch die Geometrie der Rissspitze eine entscheidende Rolle bei der Bestimmung der Aktivierungsbarriere für Rissausbreitung spielt. Durch Berücksichtigung der Auswirkungen von Randbereich und Rissspitzengeometrie ist es möglich, die kritischen Werte für den Bruch zu bestimmen und die zugrunde liegenden Mechanismen der Rissausbreitung genauer zu verstehen. Insgesamt bietet die flexible Anpassung des Randbereiches die Möglichkeit, Brüche in komplexen spröden Materialien und Strukturen zu untersuchen und unser Verständnis der grundlegenden Prozesse zu verbessern
Die Rolle von mikro-RNAs während der B-Zell-Entwicklung
Get PDFB cell development in vertebrates is a complex process, involving numerous differentiation stages at many anatomical locations. Long-known regulators of B cell gene expression include transcription factor networks, cytokines, and cell surface receptors. In recent decades, small non-coding microRNAs (miRNAs) have been shown to exert an additional layer of control over gene expression and have been demonstrated to act as critical gatekeepers at various checkpoints during the tightly regulated B cell development
Simultaneous film temperature and film thickness measurements for jet impingement applications using two-color laser-induced fluorescence
Get PDFThe study investigates a jet impingement cooling process of a cylindrical geometry relevant for electric and electronic applications. The applied two-color detection technique enables a simultaneous determination of film temperature and film thickness. For this purpose, the heat transfer oil Marlotherm LH was doped with the temperature-sensitive fluorescence tracer nile red. The temperature determination was realized by suitable band pass filters. Preliminary spectral investigations were carried out in terms of varying dye concentration, temperature and film thickness. At high dye concentrations (up to 37.5 mg/L), reabsorption effects lead to a spectral shift toward higher wavelengths with increasing film thickness. Low dye concentrations (0.29 mg/L, 0.59 mg/L) show no film thickness dependent spectral shift. A film temperature investigation at low dye concentration showed no bias of the intensity ratio due to film thickness, i.e., no additional spectral shift toward lower wavelengths was observed. The investigations on the jet impingement setup revealed an increasing film temperature and decreasing film thickness with increasing solid temperature. The average film temperature increases with increasing solid temperature from 298 (solid temperature 298 K) to 308 K (solid temperature 398 K). At higher solid temperatures, the film temperature increases with distance to the stagnation zone. The average film thickness decreases with increasing solid temperature from 0.24 to 0.17 mm. At high solid temperatures, the film temperature increased with radial distance to the stagnation zone. This behavior is caused by the increasing temperature gradient with increasing solid temperature and decreasing viscosity with increasing film temperature.Open Access funding enabled and organized by Projekt DEAL.Universität der Bundeswehr München (3147
The sarcoma ring trial: a case-based analysis of inter-center agreement across 21 German-speaking sarcoma centers
Get PDFPurpose The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers. Methods In this cross-sectional case-based survey study, 5 anonymized patient cases with imaging data of localized STS were presented to MTBs of 21 German-speaking tertiary referral hospitals. Centers provided recommendations on treatment sequence and modalities, along with the consensus level within their MTB. Agreement percentages were calculated, and consensus levels were rated on a scale of 1 to 10. Results Five patient cases were discussed resulting in 105 recommendations. Agreement percentages for case 1 to 5 were 14.3%, 61.9%, 33.3%, 52.4% and 9.3%, with a median agreement percentage of 33.3%. Grouping pre- and postoperative therapies as "perioperative" and including recommendations with and without regional hyperthermia raised the median agreement to 47.6%. The mean consensus level within each center across all 5 cases was 9.5. Conclusion This first case-based analysis of inter-center agreement for STS management in German-speaking countries reveals low inter-center agreement but high intra-center consensus. Our study includes nearly all tertiary sarcoma centers in German-speaking countries, affirming its strong external validity. These findings suggest potential and clinically very relevant differences in treatment standards among sarcoma centers. Enhanced case-based exchanges and collaborative efforts are needed to reduce discrepancies and standardize the management of STS patients.Open Access funding enabled and organized by Projekt DEAL.Medizinische Fakultät Mannheim der Universität Heidelberg (8990
Skeletal muscle vulnerability in a child with Pitt-Hopkins syndrome
Get PDFBackground TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle. Method To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling. Results We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4 -mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression. Conclusion Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.Open Access funding enabled and organized by Projekt DEAL.Open Access Publication Fund of the University of Duisburg-EssenMinisterium für Kultur und Wissenschaft des Landes Nordrhein-Westfalenhttp://dx.doi.org/10.13039/501100014690ERDF; project NME-GPSGerman Society of Muscular DiseasesUniversitätsklinikum Essen (8912
How Connected Cars Could Capture Cloud Dynamics for Solar Forecasting—Evidence from Two Simulation Scenarios
Get PDFThe rapidly increasing share of fluctuating electricity from photovoltaics calls for accurate approaches to estimate cloud motion, the primary source for the varying power supply. While local sensor networks are prominent in targeting forecast horizons too short for image‐based methods, they have minimal spatial coverage. This work presents the first step towards expanding those approaches to spatially scalable sensor networks: With the motivation of using automotive light sensors as a sensor network, two excerpts from a microscopic traffic simulation serve as simulative sensor networks. A fractal‐based cloud shadow pattern passes the sensor network areas with defined velocities and directions, which shall be estimated using the cumulative mean absolute error method. The evaluation results indicate that the more extensive observation areas compensate for the dynamics in the sensor network when compared to a reference work with a static sensor grid. Furthermore, this work shows how the estimates deteriorate with lower vehicle penetration rates (PR) and longer building shadows due to a lower solar elevation angle. At a penetration rate of 40%, the root mean square errors for both sensor networks are still below 5 ms −1 . In conclusion, the spatiotemporal characteristics of a vehicle network offer a potential for estimating cloud movements.This work proposes to use sensor networks comprised of connected vehicles with light sensors for cloud shadow velocity and direction estimation. Spatiotemporal conditions are investigated in a simulative environment with a traffic simulation representing cars, a fractal cloud shadow model moving with defined velocities and directions as physical dynamics, and the cumulative mean absolute error method for capturing those dynamics. image © 2024 WILEY‐VCH Gmb
Continuity of medication information transfer and continuous medication supply during hospital-to-home transitions - nationwide surveys in hospital and community pharmacies after implementing new legal requirements in Germany
Get PDFBackground While successful information transfer and seamless medication supply are fundamental to medication safety during hospital-to-home transitions, disruptions are frequently reported. In Germany, new legal requirements came into force in 2017, strengthening medication lists and discharge summaries as preferred means of information transfer. In addition to previous regulations – such as dispensing medication at discharge by hospital pharmacies – hospital physicians were now allowed to issue discharge prescriptions to be supplied by community pharmacies. The aim of this survey study was to gain first nationwide insights into how these requirements are implemented and how they impact the continuity of medication information transfer and continuous medication supply. Methods Two nationwide self-administered online surveys of all hospital and community pharmacies across Germany were developed and conducted from April 17th to June 30th, 2023. Results Overall, 31.0% ( n = 111) of all German hospital pharmacies and 4.5% ( n = 811) of all community pharmacies participated. The majority of those hospital pharmacies reported that patients who were discharged were typically provided with discharge summaries (89.2%), medication lists (59.5%) and if needed, discharge prescriptions (67.6%) and/or required medication (67.6%). About every second community pharmacy (49.0%) indicated that up to half of the recently discharged patients who came to their pharmacy typically presented medication lists. 34.0% of the community pharmacies stated that they typically received a discharge summary from recently discharged patients at least once per week. About three in four community pharmacies (73.3%) indicated that most discharge prescriptions were dispensed in time. However, one-third (31.0%) estimated that half and more of the patients experienced gaps in medication supply. Community pharmacies reported challenges with the legal requirements – such as patients´ poor comprehensibility of medication lists, medication discrepancies, unmet formal requirements of discharge prescriptions, and poor accessibility of hospital staff in case of queries. In comparison, hospital pharmacies named technical issues, time/personnel resources, and deficits in patient knowledge of medication as difficulties. Conclusion According to the pharmacies´ perceptions, it can be assumed that discontinuation in medication information transfer and lack of medication supply still occur today during hospital-to-home transitions, despite the new legal requirements. Further research is necessary to supplement these results by the perspectives of other healthcare professionals and patients in order to identify efficient strategies.Open Access funding enabled and organized by Projekt DEAL.Medizinische Fakultät Heidelberg der Universität Heidelberg (9149
Bromine Adsorption and Thermal Stability on Rh(111): A Combined XPS, LEED and DFT Study
Get PDFThis study addresses a fundamental question in surface science: the adsorption of halogens on metal surfaces. Using synchrotron radiation‐based high‐resolution X‐ray photoelectron spectroscopy (XPS), temperature‐programmed XPS, low‐energy electron diffraction (LEED) and density functional theory (DFT) calculations, we investigated the adsorption and thermal stability of bromine on Rh(111) in detail. The adsorption of elemental bromine on Rh(111) at 170 K was followed in situ by XPS in the Br 3d region, revealing two individual, coverage‐dependent species, which we assign to fcc hollow‐ and bridge‐bound atomic bromine. In addition, we find a significant shift in binding energy upon increasing coverage due to adsorbate‐adsorbate interactions. Subsequent heating shows a high thermal stability of bromine on Rh(111) up to above 1000 K, indicating strong covalent bonding. To complement the XPS data, LEED was used to study the long‐range order of bromine on Rh(111): we observe a (√3×√3)R30° structure for low coverages (≤0.33 ML) and a star‐shaped compression structure for higher coverages (0.33–0.43 ML). Combining LEED and DFT calculations, we were able to visualize bromine adsorption on Rh(111) in real space for varying coverages.The adsorption and thermal stability of bromine on Rh(111) is investigated by synchrotron radiation‐based XPS, LEED and DFT. Depending on the coverage, four different superstructures are observed. At low coverages, bromine occupies fcc hollow sites while, at higher coverages, a compression of the overlayer leads to bridge‐bound bromine atoms. Br/Rh(111) shows a high thermal stability, which implies strong covalent bonding. imageBESSY IIHelmholtz-Zentrum Berlin (HZB) für Materialien und EnergieDFG http://dx.doi.org/10.13039/501100001659SFB 953SFB 1452Fonds der Chemischen Industrie http://dx.doi.org/10.13039/10001899
Mode of Metal Ligation Governs Inhibition of Carboxypeptidase A
Get PDFCarboxypeptidase is a Zn-dependent protease that specifically recognises and hydrolyses peptides with a hydrophobic side chain at the C-terminal residue. According to hydrolysis mechanisms proposed in the literature, catalysis requires a water molecule to be close to the Zn ion so as to be activated as a nucleophile. Among small molecules that resemble the slowly hydrolysed Gly-Tyr peptide, which have been previously designed as inhibitors and characterised structurally, a variant with the terminal amino acid in a D-configuration has been the most effective. Our molecular dynamics simulations of carboxypeptidase complexed with different variants of those inhibitor ligands as well as variants of the Gly-Tyr peptide show that the strength of the inhibitory effect is not related to the binding strength of the ligand. Our data rather support an earlier notion that the inhibition is, at least partially, due to blocking a coordination site at the Zn ion by the ligand coordinating the metal ion in a bidentate fashion.This research was funded by the NHR Graduate School of National High Performance Computing (NHR) and the Deutscher Akademischer Austausch Dienst, grant ID 91832151.NHR Graduate School of National High Performance ComputingDeutscher Akademischer Austausch Diens