Brownian Dynamics Simulations including Explicit Atoms for Modeling Transport through Nanopores

• Applicant: Professor Dr. Ulrich Kleinekathöfer
• Subject Area: Biophysics ; Biochemistry
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452270316

• Final Report Year: 2025

Final Report Abstract

Gram-negative bacteria contain the outer membrane as their outermost barrier, which must allow the exchange of substrates with its environment in order to survive. Thus, the outer membrane acts as a molecular sieve for water soluble molecules. To study permeation through such channels, one wants to represent the system atom by atom, while at the same time computational efficiency is an issue. To this end, we have tested and applied the so-called Brownian Dynamics with Explicit Atoms (BRODEA) approach to the translocation of antibiotic molecules through membrane pores, but also to the transport through and blocking of a very large channel in Bacillus anthracis. The numerical speed of the BRODEA approach allows much longer simulation times, which would be computationally extremely expensive using all-atom molecular dynamics simulations. The Brownian dynamics scheme allowed direct simulation of the translocation of the small charged fosfomycin antibiotic molecules. For applied electric fields, the resulting numbers agreed quite well with results from all-atom simulations and, more importantly, from electrophysiological experiments. The BRODEA scheme was also used to analyze a number of antibiotic molecules in terms of their permeation into bacteria. Again, the results correlate quite well with the corresponding permeation rates from experiments. The BRODEA approach can show its full strength when applied to large systems where some flexibility in the pore residues or the substrate molecule is still important. One such system is the anthrax toxin channel, to which we applied the hybrid scheme. Experiments suggested a binding site for quinoline molecules, which is an important finding in the search for new blockers targeting the anthrax channel. Applied field Brownian dynamics simulations allowed us to determine flux rates and free energy profiles that would have been impossible with all-atom simulations. Despite the successes of the BRODEA approach, one shortcoming became apparent. Molecular dynamics simulations showed that movements of the L3 loop in the porin channels can lead to accelerated passage of positively charged molecules. Such results require a flexible description of at least part of the pore. We have shown that antibiotic-induced dynamics of the L3 loop are operative in several porins. However, sequence and structural differences influence the magnitude of L3 loop fluctuations and thus the effect on antibiotic translocation.

Publications

• Millisecond-Long Simulations of Antibiotics Transport through Outer Membrane Channels. Journal of Chemical Theory and Computation, 17(1), 549-559.
  Golla, Vinaya Kumar; Prajapati, Jigneshkumar Dahyabhai & Kleinekathöfer, Ulrich
  
• Improved Sampling and Free Energy Estimates for Antibiotic Permeation through Bacterial Porins. Journal of Chemical Theory and Computation, 17(7), 4564-4577.
  Acharya, Abhishek; Prajapati, Jigneshkumar Dahyabhai & Kleinekathöfer, Ulrich
  
• Atomistic Simulation of Molecules Interacting with Biological Nanopores: From Current Understanding to Future Directions. The Journal of Physical Chemistry B, 126(22), 3995-4008.
  Acharya, Abhishek; Prajapati, Jigneshkumar Dahyabhai & Kleinekathöfer, Ulrich
  
• Changes in Salt Concentration Modify the Translocation of Neutral Molecules through a ΔCymA Nanopore in a Non-monotonic Manner. ACS Nano, 16(5), 7701-7712.
  Prajapati, Jigneshkumar Dahyabhai; Pangeni, Sushil; Aksoyoglu, Mehmet Alphan; Winterhalter, Mathias & Kleinekathöfer, Ulrich
  
• Conformational Dynamics of Loop L3 in OmpF: Implications toward Antibiotic Translocation and Voltage Gating. Journal of Chemical Information and Modeling, 63(3), 910-927.
  Acharya, Abhishek; Ghai, Ishan; Piselli, Claudio; Prajapati, Jigneshkumar Dahyabhai; Benz, Roland; Winterhalter, Mathias & Kleinekathöfer, Ulrich
  
• Antibiotic Charge Profile Determines the Extent of L3 Dynamics in OmpF: An Expedited Passage for Molecules with a Positive Charge. The Journal of Physical Chemistry B, 127(50), 10766-10777.
  Acharya, Abhishek; Jana, Kalyanashis & Kleinekathöfer, Ulrich
  
• Fast prediction of antibiotic permeability through membrane channels using Brownian dynamics. Biophysical Journal, 122(14), 2996-3007.
  Acharya, Abhishek; Jana, Kalyanashis; Gurvic, Dominik; Zachariae, Ulrich & Kleinekathöfer, Ulrich
  
• Molecular Mechanism of Ciprofloxacin Translocation Through the Major Diffusion Channels of the ESKAPE Pathogens Klebsiella pneumoniae and Enterobacter cloacae. The Journal of Physical Chemistry B, 128(35), 8376-8387.
  Acharya, Abhishek; Behera, Pratik Kumar & Kleinekathöfer, Ulrich