According to a widely accepted paradigm of microbiology, steady-state growth rates are determined solely by current growth conditions and adaptations between growth states are rapid, as recently recapitulated by simple resource allocation models. However, even in microbes overlapping regulatory networks can yield multi-stability or long-term cellular memory. Species like and "distinguish" distinct histories for the commitment to sporulation, but it is unclear if these states can persist over many generations.
View Article and Find Full Text PDFCyclic peptides extend the druggable target space due to their size, flexibility, and hydrogen-bonding capacity. However, these properties impact also their passive membrane permeability. As the "journey" through membranes cannot be monitored experimentally, little is known about the underlying process, which hinders rational design.
View Article and Find Full Text PDFCyclic peptides have the potential to vastly extend the scope of druggable proteins and lead to new therapeutics for currently untreatable diseases. However, cyclic peptides often suffer from poor bioavailability. To uncover design principles for permeable cyclic peptides, a promising strategy is to analyze the conformational dynamics of the peptides using molecular dynamics (MD) and Markov state models (MSMs).
View Article and Find Full Text PDFPhys Chem Chem Phys
January 2022
Molecular dynamics (MD) simulations are a powerful tool to follow the time evolution of biomolecular motions in atomistic resolution. However, the high computational demand of these simulations limits the timescales of motions that can be observed. To resolve this issue, so called enhanced sampling techniques are developed, which extend conventional MD algorithms to speed up the simulation process.
View Article and Find Full Text PDFProteins with large and flat binding sites as well as protein-protein interactions are considered ' undruggable ' with conventional small-molecule drugs. Cyclic peptides have been found to be capable of binding to such targets with high affinity, making this class of compounds an interesting source for possible therapeutics. However, the oftentimes poor passive membrane permeability of cyclic peptides still imposes restrictions on the applicability of cyclic peptide drugs.
View Article and Find Full Text PDFEnsembler is a Python package that enables method prototyping using 1D and 2D model systems and allows deepening of the understanding of different molecular dynamics (MD) methods, starting from basic techniques to enhanced sampling and free-energy approaches. The ease of installing and using the package increases shareability, comparability, and reproducibility of scientific code developments. Here, we describe the implementation and usage of the package and provide an application example for free-energy calculation.
View Article and Find Full Text PDFThermally driven processes of molecular systems include transitions of energy barriers on the microsecond timescales and higher. Sufficient sampling of such processes with molecular dynamics simulations is challenging and often requires accelerating slow transitions using external biasing potentials. Different dynamic reweighting algorithms have been proposed in the past few years to recover the unbiased kinetics from biased systems.
View Article and Find Full Text PDFAppl Environ Microbiol
April 2020
Changing nutritional conditions challenge microbes and shape their evolutionary optimization. Here, we used real-time metabolomics to investigate the role of glycogen in the dynamic physiological adaptation of to fluctuating nutrients following carbon starvation. After the depletion of environmental glucose, we found significant metabolic activity remaining, which was linked to rapid utilization of intracellular glycogen.
View Article and Find Full Text PDFPredicting the costructure of small-molecule ligands and their respective target proteins has been a long-standing problem in drug discovery. For weak binding compounds typically identified in fragment-based screening (FBS) campaigns, determination of the correct binding site and correct binding mode is usually done experimentally via X-ray crystallography. For many targets of pharmaceutical interest, however, establishing an X-ray system which allows for sufficient throughput to support a drug discovery project is not possible.
View Article and Find Full Text PDFBackground: Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic features, including sequence composition and conservation.
View Article and Find Full Text PDFColor-tuned variants of channelrhodopsins allow for selective optogenetic manipulation of different host cell populations. Chrimson is the channelrhodopsin with the longest wavelength absorbance maximum. We characterize its photochemical properties at different pH values corresponding to two protonation states of the counterion for the protonated Schiff base.
View Article and Find Full Text PDFThe fusion of lipid membranes is opposed by high energetic barriers. In living organisms, complex protein machineries carry out this biologically essential process. Here we show that membrane-spanning carbon nanotubes (CNTs) can trigger spontaneous fusion of small lipid vesicles.
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