Abstract
Modern medicine relies upon antibiotics, but we have arrived to the point where our inability to come up with new effective molecules against resistant pathogens, together with the declining private investment, is resulting in the number of untreatable infections increasing worldwide at worrying pace. Among other pathogens, widely recognized institutions have indicated Gram-negative bacteria as particularly challenging, due to the presence of the outer membrane. The very first step in the action of every antibiotic or adjuvant is the permeation through this membrane, with small hydrophilic drugs usually crossing through protein channels. Thus, a detailed understanding of their properties at a molecular level is crucial. By making use of Molecular Dynamics simulations, we compared the two main porins of four members of the Enterobacteriaceae family, and, in this paper, we show their shared geometrical and electrostatic characteristics. Then, we used metadynamics simulations to reconstruct the free energy for permeation of selected diazobicyclooctans through OmpF. We demonstrate how porins features are coupled to those of the translocating species, modulating their passive permeation. In particular, we show that the minimal projection area of a molecule is a better descriptor than its molecular mass or the volume. Together with the magnitude and orientation of the electric dipole moment, these are the crucial parameters to gain an efficient compensation between the entropic and enthalpic contributions to the free energy barrier required for permeation. Our results confirm the possibility to predict the permeability of molecules through porins by using a few molecular parameters and bolster the general model according to which the free energy increase is mostly due to the decrease of conformational entropy, and this can be compensated by a favorable alignment of the electric dipole with respect to the channel intrinsic electric field.
Highlights
Antibiotics have been regarded as magic bullets to treat infections for almost the entire 20th century.Modern medicine relies upon them, but due to their spread misuse, we have arrived to the point where almost all antibacterial drugs developed so far have been followed by detection of resistance [1,2].Resistance is related to bacteria innate evolution, and, briefly, it is a condition by which susceptibility to the antibiotic is reduced
The system was oriented in order to center the protein at the origin of the coordinate system and align the channel diffusion axis along the z-axis, z positive values refer to the extracellular vestibule (EV), and z negative values refer to the periplasmic vestibule (PV)
We demonstrated with all-atom molecular dynamics simulations that the OmpF/OmpC orthologs from Enterobacteriaceae species share common geometrical and electrostatic properties
Summary
Resistance is related to bacteria innate evolution, and, briefly, it is a condition by which susceptibility to the antibiotic is reduced This is accelerated by the extensive use of antibiotics in human and human-related activities, meaning that we will always need new antibiotics. High-throughput screening protocols are looked with great hope as a way to identify novel drug scaffolds, but these protocols need to be fed with proper selection rules, otherwise the risk is high that they can be biased [4,5]. Along this direction, some preliminary “rules for good antibiotics” were recently proposed [6,7]. The problem is urgent, since the pipeline is virtually empty of new scaffolds
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