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Microscopic Mechanism of Antibiotics Translocation through a Porin

Matteo Ceccarelli ^*, Christophe Danelon , Alessandro Laio ^* and Michele Parrinello ^*

^* Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich, USI Campus, Lugano, Switzerland; and Institut Pharmacologie et Biologie Structurale, 31077 Toulouse, France

Correspondence: Address reprint requests to Prof. Michele Parrinello, Computational Science, Dept. of Chemistry and Applied Biosciences, ETH Zurich, USI Campus, Via Buffi 13, CH 6904 Lugano, Switzerland. Tel.: 41-91-9138 801; Fax: 41-91-9138 817; E-mail: parrinello{at}phys.chem.ethz.ch.

OmpF from the outer membrane of Escherichia coli is a general porin considered to be the main pathway for ß-lactam antibiotics. The availability of a high-resolution crystal structure of OmpF and new experimental techniques at the single-molecule level have opened the way to the investigation of the microscopic mechanisms that allow the passage of antibiotics through bacterial pores. We applied molecular dynamics simulations to investigate the translocation process of ampicillin (Amp) through OmpF. Using a recent algorithm capable of accelerating molecular dynamics simulations we have been able to obtain a reaction path for the translocation of Amp through OmpF. The mechanism of passage depends both on the internal degrees of freedom of Amp and on interactions of Amp with OmpF. Understanding this mechanism would help us design more efficient antibiotics and shed light on nature's way of devising channels able to enhance the transport of molecules through membranes.

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