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G protein-coupled receptors (GPCRs) play a crucial role in modulating physiological responses and serve as the main drug target. Specifically, salmeterol and salbutamol which are used for the treatment of pulmonary diseases, exert their effects by activating the GPCR β2-adrenergic receptor (β2AR). In our study, we employed coarse-grained molecular dynamics simulations with the Martini 3 force field to investigate the dynamics of drug molecules in membranes in presence and absence of β2AR. Our simulations reveal that in more than 50% of the flip-flop events the drug molecules use the β2AR surface to permeate the membrane. The pathway along the GPCR surface is significantly more energetically favorable for the drug molecules, which was revealed by umbrella sampling simulations along spontaneous flip-flop pathways. Furthermore, we assessed the behavior of drugs with intracellular targets, such as kinase inhibitors, whose therapeutic efficacy could benefit from this observation. In summary, our results show that β2AR surface interactions can significantly enhance membrane permeation of drugs, emphasizing their potential for consideration in future drug development strategies.
We propose a generalized modeling framework for the kinetic mechanisms of transcriptional riboswitches. The formalism accommodates time-dependent transcription rates and changes of metabolite concentration and permits incorporation of variations in transcription rate depending on transcript length. We derive explicit analytical expressions for the fraction of transcripts that determine repression or activation of gene expression, pause site location and its slowing down of transcription for the case of the (2’dG)-sensing riboswitch from Mesoplasma florum. Our modeling challenges the current view on the exclusive importance of metabolite binding to transcripts containing only the aptamer domain. Numerical simulations of transcription proceeding in a continuous manner under time-dependent changes of metabolite concentration further suggest that rapid modulations in concentration result in a reduced dynamic range for riboswitch function regardless of transcription rate, while a combination of slow modulations and small transcription rates ensures a wide range of finely tuneable regulatory outcomes.