The number of pathogens developing multiple drug resistance is ever increasing. The impact on healthcare systems is huge and the need for novel antibiotics as well a new way to develop them is urgent, especially against Gram- negative bacteria. The first defense of these bacteria is the outer membrane, where unspecific protein channels (porins) modulate nutrients passive diffusion. Also polar antibiotics enter through this path and down-regulation and/or mutation of porins are very common in drug resistant strains. Our inability to come up with novel effective antibiotics mostly relies upon the insufficient comprehension of the key molecular features enabling better penetra- tion through porins. Molecular dynamics simulations offer an extraordinary tool in the study of the dynamics of biological systems; however, one of the major drawbacks of this method is that its use is currently restricted to study time scales of the order of microsecond. Enhanced sampling methods like Metadynamics have been recently used to inves- tigate the diffusion of antibiotics through bacterial porins. The main limitation is that dynamical properties can- not be estimated because of the different potential that the systems under study are experiencing. Recently, the scope of Metadynamics has been extended. By applying an a posteriori analysis one can obtain rates of transitions and rate-limiting steps of the process under study, directly comparable with kinetic data extracted from electro- physiology experiments. In this work, we apply this method to the study of the permeability of Escherichia coli's OmpF with respect to Meropenem, finding good agreement with the residence time obtained analyzing experi- mental current noise

A kinetic model for molecular diffusion through pores

D'AGOSTINO, TOMMASO;SALIS, SAMUELE;CECCARELLI, MATTEO
2016

Abstract

The number of pathogens developing multiple drug resistance is ever increasing. The impact on healthcare systems is huge and the need for novel antibiotics as well a new way to develop them is urgent, especially against Gram- negative bacteria. The first defense of these bacteria is the outer membrane, where unspecific protein channels (porins) modulate nutrients passive diffusion. Also polar antibiotics enter through this path and down-regulation and/or mutation of porins are very common in drug resistant strains. Our inability to come up with novel effective antibiotics mostly relies upon the insufficient comprehension of the key molecular features enabling better penetra- tion through porins. Molecular dynamics simulations offer an extraordinary tool in the study of the dynamics of biological systems; however, one of the major drawbacks of this method is that its use is currently restricted to study time scales of the order of microsecond. Enhanced sampling methods like Metadynamics have been recently used to inves- tigate the diffusion of antibiotics through bacterial porins. The main limitation is that dynamical properties can- not be estimated because of the different potential that the systems under study are experiencing. Recently, the scope of Metadynamics has been extended. By applying an a posteriori analysis one can obtain rates of transitions and rate-limiting steps of the process under study, directly comparable with kinetic data extracted from electro- physiology experiments. In this work, we apply this method to the study of the permeability of Escherichia coli's OmpF with respect to Meropenem, finding good agreement with the residence time obtained analyzing experi- mental current noise
Porins, Molecular dynamics, Kinetics, Transport
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/144144
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