Brownian Dynamics Approach Including Explicit Atoms for Studying Ion Permeation and Substrate Translocation across Nanopores.

A Brownian dynamics (BD) approach including explicit atoms called BRODEA is presented to model ion permeation and molecule translocation across a nanopore confinement. This approach generalizes our previous hybrid molecular dynamics-Brownian dynamics framework ( J. Chem. Theory Comput. 2016, 12, 2401) by incorporating a widespread and enhanced set of simulation schemes based on several boundary conditions and electrostatic models, as well as a temperature accelerated method for sampling free energy surfaces and determining substrate translocation pathways. As a test case, BRODEA was applied to study the ion diffusion as well as to ciprofloxacin and enrofloxacin transport through the outer membrane porin OmpC from E. coli. The equivalence between the different simulation schemes was demonstrated and their computational efficiency evaluated. The BRODEA results are able to reproduce the main features of the ion currents and free energy surfaces determined by all-atom molecular dynamics simulations and validated by experiments. Furthermore, the BRODEA results are able to determine the ciprofloxacin and enrofloxacin permeation pathways showing a remarkable agreement with the results obtained from a computational protocol that combines metadynamics and a zero-temperature string method ( J. Chem. Theory Comput. 2017, 13, 4553; J. Phys. Chem. B 2018, 122, 1417). To our knowledge, this is the first time such antibiotic permeation pathways have been characterized by a technique based on Brownian dynamics.

BROMOCEA Code: An Improved Grand Canonical Monte Carlo/Brownian Dynamics Algorithm Including Explicit Atoms.

All-atom molecular dynamics simulations have a long history of applications studying ion and substrate permeation across biological and artificial pores. While offering unprecedented insights into the underpinning transport processes, MD simulations are limited in time-scales and ability to simulate physiological membrane potentials or asymmetric salt solutions and require substantial computational power. While several approaches to circumvent all of these limitations were developed, Brownian dynamics simulations remain an attractive option to the field. The main limitation, however, is an apparent lack of protein flexibility important for the accurate description of permeation events. In the present contribution, we report an extension of the Brownian dynamics scheme which includes conformational dynamics. To achieve this goal, the dynamics of amino-acid residues was incorporated into the many-body potential of mean force and into the Langevin equations of motion. The developed software solution, called BROMOCEA, was applied to ion transport through OmpC as a test case. Compared to fully atomistic simulations, the results show a clear improvement in the ratio of permeating anions and cations. The present tests strongly indicate that pore flexibility can enhance permeation properties which will become even more important in future applications to substrate translocation.