Ulrich Kleinekathöfer

• Prof. Dr.
• Professor (Full) at Constructor University

The estimation of accurate free energies for antibiotic permeation via the bacterial outer-membrane porins has proven to be challenging. Atomistic simulations of the process suffer from sampling issues that are typical of systems with complex and slow dynamics, even with the application of advanced sampling methods. Ultimately, the objective is to...

Multi‐fidelity methods in machine learning (ML) have seen increasing usage for the prediction of quantum chemical properties. These methods, such as ‐ML and Multifidelity Machine Learning (MFML), have been shown to significantly reduce the computational cost of generating training data. This work implements and analyzes several multi‐fidelity metho...

Multifidelity methods in machine learning (ML) have seen an increasing usage for the prediction of quantum chemical properties. These methods, such as ∆-ML and multifidelity ML, have been shown to significantly reduce the computational cost of generating training data. This work implements and analyzes several multifidelity methods including ∆-ML a...

The astonishing efficiency of exciton transfer in light-harvesting (LH) complexes has prompted a multitude of experimental and theoretical studies over the past two decades. However, the revision of the long-held role of electronic coherences calls for alternative explanations. In this study, we investigate the exciton motion through the LH2 comple...

Although recent advances in simulating open quantum systems have led to significant progress, the applicability of numerically exact methods is still restricted to rather small systems. Hence, more approximate methods remain relevant due to their computational efficiency, enabling simulations of larger systems over extended timescales. In this stud...

Although recent advances in simulating open quantum systems have lead to significant progress, the applicability of numerically exact methods is still restricted to rather small systems. Hence, more approximate methods remain relevant due to their computational efficiency, enabling simulations of larger systems over extended timescales. In this stu...

Experimental studies on the translocation and accumulation of antibiotics in Gram-negative bacteria have revealed details of the properties that allow efficient permeation through bacterial outer membrane porins. Among the major outer membrane diffusion channels, OmpF has been extensively studied to understand the antibiotic translocation process....

Many important processes in cells depend on the transfer of protons through water wires embedded in transmembrane proteins. Herein, we have performed more than 55 μs all-atom simulations of the light-harvesting complex of a diatom, i.e., the fucoxanthin and chlorophyll a/c binding protein (FCP) from the marine diatom Phaeodactylum tricornutum. Diat...

A trajectory surface hopping approach, which uses machine learning to speed up the most time-consuming steps, has been adopted to investigate the exciton transfer in light-harvesting systems.

In this study, the site energy fluctuations, energy transfer dynamics, and some spectroscopic properties of the minor light-harvesting complex CP24 in a membrane environment were determined. For this purpose, a 3 μs-long classical molecular dynamics simulation was performed for the CP24 complex. Furthermore, using the density functional tight bindi...

Machine learning (ML) provides access to fast and accurate quantum chemistry (QC) calculations for various properties of interest such as excitation energies. It is often the case that high accuracy in prediction using a ML model, demands a large and costly training set. Various solutions and procedures have been presented to reduce this cost. Thes...

Diatoms are one of the most abundant photosynthetic organisms on earth and contribute largely to atmospheric oxygen production. They contain fucoxanthin and chlorophyll-a/c binding proteins (FCPs) as light-harvesting complexes with a remarkable adaptation to the fluctuating light on ocean surfaces. To understand the basis of the photosynthetic proc...

The Förster resonance energy transfer (FRET) between the Fenna–Matthews–Olson (FMO) protein complex and the chlorosomal baseplate (CBP) is investigated by using an idealized model. This simplified model is based on crystal structure and molecular dynamics conformations. Some of the further input, such as the transition dipole moments, was extracted...

For a detailed understanding of many processes in nature involving, for example, energy or electron transfer, the theory of open quantum systems is of key importance. For larger systems, an accurate description of the underlying quantum dynamics is still a formidable task, and, hence, approaches employing machine learning techniques have been devel...

Vitamin B 12 (cobalamin) is required for most human gut microbes, many of which are dependent on scavenging to obtain this vitamin. Since bacterial densities in the gut are extremely high, competition for this keystone micronutrient is severe. Contrasting with Enterobacteria, members of the dominant genus Bacteroides often encode several BtuB vitam...

Correction for 'Benchmark and performance of long-range corrected time-dependent density functional tight binding (LC-TD-DFTB) on rhodopsins and light-harvesting complexes' by Beatrix M. Bold et al., Phys. Chem. Chem. Phys., 2020, 22, 10500-10518, https://doi.org/10.1039/C9CP05753F.

Diatoms are one of the most abundant photosynthetic organisms on earth and contribute largely to the atmospheric oxygen production. They contain fucoxanthin and chlorophyll-a/c binding proteins (FCPs) as light-harvesting complexes with a remarkable adaptation to the fluctuating light on ocean surfaces. To understand the basis of the photosynthetic...

The accurate but fast calculation of molecular excited states is still a very challenging topic. For many applications, detailed knowledge of the energy funnel in larger molecular aggregates is of key importance requiring highly accurate excited state energies. To this end, machine learning techniques can be an extremely useful tool though the cost...

The efficient permeation across the Gram-negative bacterial membrane is an important step in the overall process of antibacterial action of a molecule and the one that has posed a significant hurdle on the way towards approved antibiotics. Predicting the permeability for a large library of molecules and assessing the effect of different molecular t...

In the present work, we delineate the molecular mechanism of a bulky antibiotic permeating through a bacterial channel and uncover the role of conformational dynamics of the constriction loop in this process. Using the temperature accelerated sliced sampling approach, we shed light onto the dynamics of the L3 loop, in particular the F118 to S125 se...

Vitamin B12 (cobalamin) is the most complex vitamin and essential for many human gut microbes. However, cobalamin is synthesised only by a limited number of bacteria, making many gut microbes dependent on scavenging to meet their cobalamin requirements. Since bacterial densities in the gut are extremely high, competition for cobalamin is severe, ma...

Pseudomonas aeruginosa is a Gram-negative bacterium with an intrinsic resistance towards antibiotics due to the lack of a large diffusion pores. Exchange of substances with the environment is done mainly through a set of narrow and substrate-specific porins in its outer membrane that filter molecules according to their size and chemical composition...

In this mini review, we focus on recent advances in the atomistic modeling of biological light-harvesting (LH) complexes. Because of their size and sophisticated electronic structures, multiscale methods are required to investigate the dynamical and spectroscopic properties of such complexes. The excitation energies, in this context also known as s...

Tailored transmembrane alpha-helical pores with desired structural and functional versatility have promising applications in nanobiotechnology. Herein, we present a transmembrane pore DpPorA, based on the natural pore PorACj, built from D-amino acid α-helical peptides. Using single-channel current recordings, we show that DpPorA peptides self-assem...

Chirality is essential in nearly all biological organizations and chemical reactions but is rarely considered due to technical limitations in identifying L/D isomerization. Using OmpF, a membrane channel from Escherichia coli with an electrostatically asymmetric constriction zone, allows discriminating chiral amino acids in a single peptide. The he...

Simulations of charge transport through DNA wires face many challenges due to limitations in the description of coherent tunneling, environmental influence and lead-molecule contacts. This article proposes a novel pathway of observing transverse transport through nucleobase-pairs of a DNA molecule to avoid most of these challenges. A total of six s...

Biological nanopores have been at the focus of numerous studies due to their role in many biological processes as well as their (prospective) technological applications. Among many other topics, recent studies on nanopores have addressed two key areas: antibiotic permeation through bacterial channels and sensing of analytes. Although the two areas...

Besides absorbing light, the core antenna complex CP43 of photosystem II is of great importance in transferring excitation energy from the antenna complexes to the reaction center. Excitation energies, spectral densities and linear absorption spectra of the complex have been evaluated by a multiscale approach. In this scheme, quantum mechanics/mole...

Chirality is essential in nearly all biological organization and chemical reaction but is rarely considered due to technical limitations in identifying L/D isomerization. Using OmpF, a membrane channel from E. coli with an electrostatically asymmetric constriction zone, allows discriminating chiral amino acids in a single peptide. The heterogeneous...

We numerically isolate the limits of validity of the Landauer approximation to describe charge transport along molecular junctions in condensed phase environments. To do so, we contrast Landauer with exact time-dependent non-equilibrium Green’s function quantum transport computations in a two-site molecular junction subject to exponentially correla...

The real use of nanoelectronics with organic molecules as a replacement of conventional silicon technology faces many challenges because of complications in synthesis and fabrication processes, short stability, junction breakdown, large fabrication costs and environmental influences. The present work aims at proposing a novel alternative by studyin...

Light harvesting as the first step in photosynthesis is of prime importance for life on earth. For a theoretical description of photochemical processes during light harvesting, spectral densities are key quantities. They serve as input functions for modeling the excitation energy transfer dynamics and spectroscopic properties. Herein, a recently de...

Antibiotics enter into bacterial cells via protein channels that serve as low-energy pathways through the outer membrane, which is otherwise impenetrable. Insights into the molecular mechanisms underlying the transport processes are vital for the development of effective antibacterials. A much-desired prerequisite is an accurate and reproducible de...

Light harvesting as the first step in photosynthesis is of prime importance for life on earth. For a theoretical description of photochemical processes during light harvesting, spectral densities are key quantities. They serve as input functions for modeling the excitation energy transfer dynamics and spectroscopic properties. Herein, a recently de...

Photosynthetic processes are driven by sunlight. Too little of it and the photosynthetic machinery cannot produce the reductive power to drive the anabolic pathways. Too much sunlight and the machinery can get damaged. In higher plants, the major Light-Harvesting Complex (LHCII) efficiently absorbs the light energy, but can also dissipate it when i...

Despite tremendous successes in the field of antibiotic discovery seen in the previous century, infectious diseases have remained a leading cause of death. More specifically, pathogenic Gram-negative bacteria have become a global threat due to their extraordinary ability to acquire resistance against any clinically available antibiotic, thus urging...

Quantifying the passage of the large peptide protamine (Ptm) across CymA, a passive channel for cyclodextrin uptake, is in the focus of this study. Using a reporter‐pair‐based fluorescence membrane assay we detected the entry of Ptm into liposomes containing CymA. The kinetics of the Ptm entry was independent of its concentration suggesting that th...

Quantifying the passage of the large peptide protamine (Ptm) across CymA, a passive channel for cyclodextrin uptake, is in the focus of this study. Using a reporter‐pair based fluorescence membrane assay we detected the entry of Ptm into liposomes containing CymA. The kinetics of the Ptm entry was independent of its concentration suggesting that th...

Photosynthetic processes are driven by sunlight. Too little of it and the photosynthetic machinery cannot produce the reductive power to drive the anabolic pathways. Too much sunlight and the machinery can get damaged. In higher plants, the major Light Harvesting Complex (LHCII) efficiently absorbs the light energy, but can also dissipate it when i...

To reach their target site inside Gram-negative bacteria, almost all antibiotics need to cross the outer membrane. Computational modeling of such processes can be numerically demanding due to the size of the systems and especially due to the timescales involved. Recently, a hybrid Brownian and molecular dynamics approach, i.e., Brownian dynamics in...

Quantifying the passage of the large peptide protamine (Ptm) across CymA, a passive channel for cyclodextrin uptake, is in the focus of this study. Using a reporter-pair based fluorescence membrane assay we detected the entry of Ptm into liposomes containing CymA. The kinetics of the Ptm entry was independent of its concentration suggesting that th...

The permeation of (neutral) molecules through nanopores in the presence of external voltages depends on several factors including pore electrostatics, electrophoretic force, and electro-osmotic drag. In earlier single-channel electrophysiology experiments, voltage-dependent asymmetric transport of neutral α-cyclodextrin (α-CD) molecules through the...

The human cathelicidin LL-37 serves a critical role in the innate immune system defending bacterial infections. LL-37 can interact with molecules of the cell wall and perforate cytoplasmic membranes resulting in bacterial cell death. To test the interactions of LL-37 and bacterial cell wall components we crystallized LL-37 in the presence of deterg...

Because of the size of light-harvesting complexes and the involvement of electronic degrees of freedom, computationally these systems need to be treated with a combined quantum-classical description. To this end, Born-Oppenheimer molecular dynamics simulations have been employed in a quantum mechanics/molecular mechanics (QM/MM) fashion for the gro...

Divalent ions are known to have a severe effect on the translocation of several antibiotics molecules into (pathogenic) bacteria. In the present study we have investigated the effect of divalent ions on the permeability of norfloxacin across the major outer membrane channels from E. coli (OmpF, OmpC) and E. aerogenes (Omp35, Omp36) at the single ch...

Porphyromonas gingivalis, an asaccharolytic member of the Bacteroidetes, is a keystone pathogen in human periodontitis that may also contribute to the development of other chronic inflammatory diseases. P. gingivalis utilizes protease-generated peptides derived from extracellular proteins for growth, but how these peptides enter the cell is not cle...

In the past two decades, molecular dynamics simulations have become the method of choice for elucidating the transport mechanisms of ions through various membrane channels. Often, these simulations heavily rely on classical non-polarizable force fields (FFs), which lack electronic polarizability in the treatment of the electrostatics. The recent ad...

The effect of divalent ions on the permeability of norfloxacin across the major outer membrane channels from E. coli (OmpF, OmpC) and E. aerogenes (Omp35, Omp36) has been investigated at the single channel level. To understand the rate limiting steps in permeation, we reconstituted single porin into planar lipid bilayers and analyzed the ion curren...

Photosynthesis is a highly optimized process from which valuable lessons can be learned about the operating principles in nature. Its primary steps involve energy transport operating near theoretical quantum limits in effi- ciency. Recently, extensive research was motivated by the hypothesis that nature used quantum coherences to direct energy tran...

Despite significant advances in resolution, the potential for cryo-electron microscopy (EM) to be used in determining the structures of protein-drug complexes remains unrealized. Determination of accurate structures and coordination of bound ligands necessitates simultaneous fitting of the models into the density envelopes, exhaustive sampling of t...

To reach their site of action, it is essential for antibiotic molecules to cross the bacterial outer membrane. The progress of enhanced sampling techniques in molecular dynamics simulations enables us to understand these translocations at an atomic level. To this end, calculations of free energy surfaces for these permeation processes are of key im...

The chromophores of rhodopsins (Rh) and light-harvesting (LH) complexes still represent a major challenge for a quantum chemical description due to their size and complex electronic structure. Since gradient corrected...

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local cur...

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local cur...

The allosteric regulation of protein function proves important in many life-sustaining processes. In plant photosynthesis, LHCII, the major antenna complex of Photosystem II, employs a delicate switch between light harvesting and photoprotective modes. The switch is triggered by an enlarged pH gra-dient (ΔpH) across the thylakoid membranes. Using m...

Porphyromonas gingivalis, an asaccharolytic Bacteroidetes, is a keystone pathogen in human periodontitis that may also contribute to the development of other chronic inflammatory diseases, such as rheumatoid arthritis, cardiovascular disease and Alzheimer's disease. P. gingivalis utilizes protease-generated peptides derived from extracellular prote...

Depending on the amount of light, the photosystem II (PSII) antennae or Light Harvesting Complexes (LHCII) switch between two states within the thylakoid membranes of higher plants, i.e., a light-harvesting and a photoprotective mode. This switch is co-regulated by a pH gradient (ΔpH) across the membrane and the interaction with the PSII subunit S...

Higher plants have evolved elaborate mechanisms to fine-tune their photosynthetic activity for the optimal yield under low light and at the same time they cope with its fluctuations. Proposals in the literature have indicated that a specific chlorophyll-a (Chl-a)/carotenoid (Car) pair within the major light harvesting complex (LHCII) of photosystem...

The time evolution in open quantum systems, such as a molecular aggregate in contact with a thermal bath, still poses a complex and challenging problem. The influence of the thermal noise can be treated using a plethora of schemes, several of which decompose the corresponding correlation functions in terms of weighted sums of exponential functions....

Protein-lipopolysaccharide (LPS) interactions play an important role in providing a stable outer membrane to Gram-negative bacteria. However, the LPS molecules are highly viscous, and sampling LPS motions is thus challenging on a microsecond timescale in simulations. To this end, we introduce a new protocol to randomly allow the LPS molecules to se...

The drug/proton antiporter AcrB, part of the major efflux pump AcrABZ-TolC in Escherichia coli, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance phenotype. However, molecular features differentiating between good and poor substrates of the pump have yet to be identified. In thi...

The time evolution in open quantum systems, such as a molecular aggregate in contact with a thermal bath, still poses a complex and challenging problem. The influence of the thermal noise can be treated using a plethora of schemes, several of which decompose the corresponding correlation functions in terms of weighted sums of exponential functions....

The current through a molecular junction can be determined numerically in a multitude of ways. Some of these methods like the Landauer scheme are only valid for coherent transport and the steady state regime while other schemes are able to treat time-dependent electronic currents across molecular junctions subject to fluctuating environments. In ti...

Fosfomycin is a frequently prescribed drug in the treatment of acute urinary tract infections. It enters the bacterial cytoplasm and inhibits the biosynthesis of peptidoglycans by targeting the MurA enzyme. Despite extensive pharmacological studies and clinical use, the permeability of fosfomycin across the bacterial outer membrane is largely unexp...

In quantum transport across molecular junctions, time-dependent effects arise mainly due to interactions with external perturbations such as pulsed laser fields or fluctuating environments. While the calculation of the charge dynamics in such an open quantum system is a complex problem, it is highly relevant for engineering nanoscale devices. Sever...

Background: Corynebacterium urealyticum, a pathogenic, multidrug resistant member of the mycolata, is known as causative agent of urinary tract infections although it is a bacterium of the skin flora. This pathogenic bacterium shares with the mycolata the property of having an unusual cell envelope composition and architecture, typical for the gen...

Research efforts to discover potential new antibiotics for Gram-negative bacteria suffer from high attrition rates due to the synergistic action of efflux systems and the limited permeability of the outer membrane (OM). One strategy to overcome the OM permeability barrier is to identify small molecules that are natural substrates for abundant OM ch...

A Brownian Dynamics (BD) approach including Explicit Atoms coined BRODEA is presented to model ion permeation and molecule translocation across a nanopore confinement. This approach generalizes our previous hybrid molecular dynamics-Brownian dynamics framework (J. Chem. Theory Comput. 12, 2401 (2016)) by incorporating a widespread and enhanced set...

The outer membrane (OM) of Gram-negative bacteria is a unique asymmetric lipid bilayer containing lipopolysaccharides (LPS) in the outer leaflet and phospholipids in the inner leaflet. Due to the lack of porins with large pores, the substrate-specific outer membrane proteins play a crucial role in the uptake of small molecules in Pseudomonas aerugi...

Although a multitude of theoretical studies exist on light-harvesting complex 2 (LH2), less is known about the light-harvesting complex 3 (LH3) of similar ring-like structure. In a comparative study of three system, i.e., the LH2 protein-pigment aggregate of the purple bacterium Rhodospirillum molischianum as well as for the LH2 and LH3 complexes o...

Research efforts to discover potential new antibiotics for Gram-negative bacteria suffer from high attrition rates due to the synergistic action of efflux systems and the limited permeability of the outer membrane (OM). One potential strategy to overcome the OM permeability barrier is to identify small molecules that are natural substrates for abun...

Chitin, an insoluble polymer of N-acetylglucosamine, is one of the most abundant biopolymers on Earth. By degrading chitin, chitinolytic bacteria such as Vibrio harveyi are critical for chitin recycling and maintenance of carbon and nitrogen cycles in the world's oceans. A decisive step in chitin degradation is the uptake of chito-oligosaccharides...

Background: Efflux pumps of the Resistance-Nodulation-cell Division superfamily confer multi-drug resistance to Gram-negative bacteria. The most-studied polyspecific transporter belonging to this class is the inner-membrane trimeric antiporter AcrB of Escherichia coli. In previous studies, a functional rotation mechanism was proposed for its funct...

In Gram-negative bacteria, the lack or quenching of antibiotics translocation across the outer membrane is one of the main factors for acquiring antibiotic resistance. An atomic level comprehension of the key features governing the transport of drugs by outer membrane protein channels will be very helpful in developing the next generation of antibi...

The Gram-negative bacterial outer membrane (OM) is a unique bilayer that forms an efficient permeation barrier to protect the cell from noxious compounds (1)(,)(2) . The defining characteristic of the OM is lipid asymmetry, with phospholipids comprising the inner leaflet and lipopolysaccharides comprising the outer leaflet (1-3) . This asymmetry is...

The rapid spreading of antimicrobial resistance in Gram-negative bacteria has become a major threat for humans as well as animals. As one of the main factors involved, the permeability of the outer membrane has attracted quite some attention recently. However, the knowledge regarding the translocation mechanisms for most available antibiotics is so...

Under phosphate-limiting conditions, the channels OprP and OprO are induced and expressed in the outer membrane of Pseudomonas aeruginosa. Despite their large homology, the phosphate-specific OprP and the diphosphate-specific OprO pores show structural differences in their binding sites situated in the constriction region. Previously, it was shown...

Dephasing processes are present in basically all applications in which quantum mechanics plays a role. These applications certainly include excitation energy and charge transfer in biological systems. Electronically coupled bacteriochlorophylls within the Fenna-Matthews-Olson and LH2 complexes as well as bilins in PE545 and PE555 aggregates are inv...

The OccK protein subfamily located in the outer membrane of Pseudomonas aeruginosa contains dynamic channels with several conformational states that range from open to closed forms. The molecular determinants of the OccK channels that contribute to the diverse gating has, however, remained elusive so far. Performing molecular dynamics simulations (...

Gram-negative bacteria feature an outer and an inner membrane. Especially the outer membrane provides an effective barrier for the entry of noxious substances, though at the same time ions, nutrients, and metabolites need to be able to get inside. Many of these substances either enter through general diffusion or through substrate-specific membrane...

Since long-lived quantum coherence have not only been observed in the Fenna-Matthews-Olson (FMO) complex of green sulfur bacteria but also in the phycoerythrin 545 (PE545) photosynthetic antenna system, the interest in these systems has been increased significantly. Moreover, similar results have been found for the PE555 complex in which the two al...

Temperature-dependent fluctuations of both site energies and electronic couplings are known to affect the excitation energy transfer in light-harvesting complexes. Environment effects on such fluctuations as well as possible spatial correlations among them are here investigated in the PE545 complex from cryptophyte algae using ensemble-averaged wav...

The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota, which has an important role in human health and nutrition. The survival of microbiota members from the dominant Gram-negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by t...

The transfer of electrons over long distances in complex molecular systems is a phenomenon of significance in both biochemistry and technology. In recent years, we have been developing efficient models to study ET in complex systems, including DNA as a prominent example. Ab initio and model approaches have been combined in an 'on the fly' calculati...

Modeling charge transport along molecular wires immersed in polarizable environments poses a grand challenge due to the high dimensionality of the problem and the various time scales involved. A previous multi-scale non-equilibrium Green’s function simulation scheme (Phys. Rev. Lett. (2012) 109, 176802) has been extended significantly, so that the...

The environmental coupling of the phycobiliprotein antenna complex PE555 and its excitonic energy transfer mechanisms are studied in detail. Molecular dynamics simulations were performed followed by calculations of the vertical transition energies along the classical ground-state trajectory. To this end, the distributions of energy levels for the P...