Macroscopic electric field inside water-filled biological nanopores

Abstract

Multi-drug resistance bacteria are a challenging problem of contemporary medicine. This is particularly critical for Gram-negative bacteria, where antibiotics are hindered by the outer membrane to reach internal targets. Here more polar antibiotics make use of nanometric water-filled channels to permeate inside. We present in this work a computational all-atom approach, using water as a probe, for the calculation of the macroscopic electric field inside water-filled channels. The method allows one to compare not only different systems but also the same system under different conditions, such as pH and ion concentration. This provides a detailed picture of electrostatics in biological nanopores shedding more light on how the charged residues of proteins determine the electric field inside, and also how medium can tune it. These details are central to unveil the filtering mechanism behind the permeation of small polar molecules through nanometric water-filled channels.

Getting Drugs through Small Pores: Exploiting the Porins Pathway in Pseudomonas aeruginosa

“…In Figure 5a Because of the abovementioned segregation of charges across the pore constriction, we expect a strong internal electric field, which was evaluated from standard MD simulations. 11 Similarly to other non-specific porins previously investigated, the highest intensity of the macroscopic electric field is located in the constriction region in the transverse direction (XY) with respect to the diffusion axis (Z). 11,28 The strength is comparable to that of OmpF When comparing ceftazidime to the other molecules used in LSA, only cefepime has a high permeation and might bind to the recognition pocket because it is structurally similar to ceftazidime ( Figure S4).…”

“…8 In our recent work, we investigated the relationship between the dipole moment of the substrates and their ability to follow the sequence of steps imposed by the internal electrostatics of non-specific porins in E. coli. [9][10][11][12] However, key functional and structural differences between these porins and specific channels require a more detailed investigation to disclose the mechanisms of permeation through the OM and to define new strategies to design effective antibiotics. The presence of multiple small pore-size channels might offer alternative pathways for antibiotics penetration in Pa, as recently demonstrated for carbapenem molecules.…”

MOMP from Campylobacter jejuni Is a Trimer of 18-Stranded β-Barrel Monomers with a Ca 2+ Ion Bound at the Constriction Zone

“…5c), the transverse internal electric field [29] of ~ 18 mV/Å was comparable to OmpC (~ 20 mV/Å) but lower than OmpF (36 mV/Å). When calcium was present, the internal electric field was reduced to almost a third of its value due to charge screening, which in turn reduced the transversal electric field in the constriction region to ~ 7 mV/Å.…”

Exploiting the Porin Pathway for Polar Compound Delivery into Gram-Negative Bacteria

“…The latter, isolated along 2 years of treatment of a patient suffering from a chronic E. coli infection, showed progressively greater resistance to the β-lactam antibiotics used for treatment, including cefotaxime, ceftazidime, ciprofloxacine, imipenem and meropenem [36]. Interestingly, while the structures of the OmpC mutants showed essentially an unchanged size [21], remarkable differences were found in the internal electric field of OmpF, OmpC and the mutants [35]. All these porins share a constriction region with net segregation of oppositely charged residues.…”

“…By using water molecules as inherent natural probes, the authors have characterized the internal electrostatics of OmpF, OmpC and some of its mutants [34,35] identified in clinically resistant strains [21]. The latter, isolated along 2 years of treatment of a patient suffering from a chronic E. coli infection, showed progressively greater resistance to the β-lactam antibiotics used for treatment, including cefotaxime, ceftazidime, ciprofloxacine, imipenem and meropenem [36].…”