Cyclic peptides extend the druggable target space due to their size, flexibility, and hydrogen-bonding capacity. However, these properties impact also passive membrane permeability. As "journey" through membranes cannot be monitored experimentally, little is known about underlying process, which hinders rational design. Here, we use molecular simulations uncover how cyclic permeate a membrane. We show that side chains can act as "molecular anchors", establishing first contact with enabling...

Changing nutritional conditions challenge microbes and shape their evolutionary optimization. Here, we used real-time metabolomics to investigate the role of glycogen in dynamic physiological adaptation Escherichia coli fluctuating nutrients following carbon starvation. After depletion environmental glucose, found significant metabolic activity remaining, which was linked rapid utilization intracellular glycogen. Glycogen depleted by 80% within minutes glucose starvation similarly...

Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, variation has been studied across human tissues genetically diverse populations. This identified disease-relevant events, as well associations between genomic features, including sequence composition conservation. However, variability single from same tissue or cell type its determinants remains poorly understood. We...

The 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 small vesicles. coarse-grained molecular dynamics simulations, find a CNT bridging between two vesicles locally perturbs their structure. Their outer leaflets merge as the pulls lipids membranes, creating an hourglass-shaped intermediate with...

Cyclic peptides have the potential to vastly extend scope of druggable proteins and lead new therapeutics for currently untreatable diseases. However, cyclic often suffer from poor bioavailability. To uncover design principles permeable peptides, a promising strategy is analyze conformational dynamics using molecular (MD) Markov state models (MSMs). Previous MD studies focused on in pure aqueous or apolar environments rationalize membrane permeability. during key steps permeation through...

Predicting 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 fragment-based screening (FBS) campaigns, determination correct site mode is usually done experimentally via X-ray crystallography. many targets pharmaceutical interest, however, establishing an system which allows for sufficient throughput to support discovery project not possible. In this case,...

Abstract Color‐tuned variants of channelrhodopsins allow for selective optogenetic manipulation different host cell populations. Chrimson is the channelrhodopsin with longest wavelength absorbance maximum. We characterize its photochemical properties at pH values corresponding to two protonation states counterion protonated Schiff base. Both will lead a functional channel opening, but route as reflected in observed spectroscopically. The light‐induced isomerization kinetics change local...

A new family of dienone musks was discovered by alkylation different aldehydes with but-3-en-1-yn-1-yllithium and subsequent domino reaction a Saucy–Marbet transfer vinylation–Claisen rearrangement an intramolecular Diels–Alder reaction, concluding Lewis acid catalyzed double-bond isomerization. The newly synthesized structures possess pleasant musk odors displaying fatty, slightly fruity green facets. Although the were predicted in silico to bind OR5AN1 receptor based on QM/MM calculations,...

Thermally driven processes of molecular systems include transitions energy barriers on the microsecond timescales and higher. Sufficient sampling such with dynamics simulations is challenging often requires accelerating slow using external biasing potentials. Different dynamic reweighting algorithms have been proposed in past few years to recover unbiased kinetics from biased systems. However, it remains an open question if how these approaches are connected. In this work, we establish link...

Ensembler is a Python package that enables method prototyping using 1D and 2D model systems allows deepening of the understanding different molecular dynamics (MD) methods, starting from basic techniques to enhanced sampling free-energy approaches. The ease installing increases shareability, comparability, reproducibility scientific code developments. Here, we describe implementation usage provide an application example for calculation. freely available on GitHub at...

Abstract Changing nutritional conditions challenge microbes and shape their evolutionary optimization. Here we investigated the role of glycogen in dynamic physiological adaptation Escherichia coli to fluctuating nutrients following carbon starvation using real-time metabolomics. We found significant metabolic activity remaining after depletion environmental glucose that was linked a rapid utilization intracellular glycogen. Glycogen depleted by 80% within minutes similarly replenished...

Proteins with large and flat binding sites as well protein–protein interactions are considered ' undruggable conventional small-molecule drugs. Cyclic peptides have been found to be capable of such targets high affinity, making this class compounds an interesting source for possible therapeutics. However, the oftentimes poor passive membrane permeability cyclic still imposes restrictions on applicability peptide Here, we describe how computational methods in combination experimental data can...

To attract children's interest in Chemistry, the youngSCS composed this easy science experiment about chromatography. It shows a beautiful and simple way behind colors explains common laboratory technique. best reach its target audience was published “Kaleio”, Swiss girl’s magazine.

Abstract Background Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, variation has been studied across human tissues genetically diverse populations. This identified disease-relevant events, as well associations between genomic variations, including sequence composition conservation. However, variability single from same tissue or cell type its determinants remain...

Cyclic peptides are able to extend the druggable space of pharmaceutical targets, due their size, conformational behavior, and high proportion hydrogen bond donors acceptors. However, for same reasons, they often suffer from poor membrane permeation thus low oral bioavailability. As permeability assays do not allow monitor pathway behavior cyclic on “journey” trough lipid membranes, little is known about underlying process, which poses a major obstacle rational design. Here, we use molecular...

According to a widely accepted paradigm of microbiology, steady-state growth rates are determined solely by current conditions1-3 and adaptations between states rapid, as recently recapitulated simple resource allocation models4. However, even in microbes overlapping regulatory networks can yield multi-stability or long-term cellular memory. Species like Listeria monocytogenes5 Bacillus subtilis "distinguish" distinct histories for the commitment sporulation6, but it is unclear if these...