Atomistic Simulation of Molecules Interacting with Biological Nanopores: From Current Understanding to Future Directions

Abstract

Biological nanopores have been at the focus of numerous studies due to their role in many biological processes as well as their (prospective) technological applications. Among many other topics, recent studies on nanopores have addressed two key areas: antibiotic permeation through bacterial channels and sensing of analytes. Although the two areas are quite far apart in terms of their objectives, in both cases atomistic simulations attempt to understand the solute dynamics and the solute−protein interactions within the channel lumen. While decades of studies on various channels have culminated in an improved understanding of the key molecular factors and led to practical applications in some cases, successful utilization is limited. In this Perspective we summarize recent progress in understanding key issues in molecular simulations of antibiotic translocation and in the development of nanopore sensors. Moreover, we comment on possible advancements in computational algorithms that can potentially resolve some of the issues.

Conformational Dynamics of Loop L3 in OmpF: Implications toward Antibiotic Translocation and Voltage Gating

“…Detailed studies on the permeation of bulky antibiotics have been difficult due to the limitations of computational simulation methods. However, the latest advances in simulation strategies have spurred renewed attempts to understand the mechanism of permeation in greater detail. − Recently, we employed the powerful temperature accelerated sliced sampling (TASS) approach and reported accurate and converged free-energy estimates for ciprofloxacin (CIP) permeation through OmpF from three independent runs within a standard error of 1 kcal/mol, indicative of a comprehensive sampling of the CIP–OmpF interactions . The TASS method, much like the umbrella sampling approach, enables a controlled sampling along the reaction path (in this case, the translocation axis), but additionally enables improved sampling along other degrees of freedom such as antibiotic rotations and antibiotic–water interactions.…”

On the Origin of Interfacial Resistance in Ideal Nanomaterials

“…MD simulations of H 2 transport in CNTs reveal this ultimate resistance to be dependent only on the fluid−solid interaction potential and to increase with an increase in the interaction strength. The understanding of interfacial resistance obtained here will be useful in the design of separation processes and nanofluidic devices and will also be valuable in analyzing transport in biological nanopores and membranes, occurring at nanometer length scales, 8 and enable advances in therapeutics and drug delivery. ■ ASSOCIATED CONTENT…”

“…Understanding the source of the interfacial resistance and unraveling the underlying mechanisms are therefore critical to the success of the quest for improved efficiency through the reduction of system size to nanoscale dimensions. This understanding will also explain some of the complexities of transport in biological systems, occurring in membrane nanopores of length of the order of a nanometer, 8 such as in aquaporins, and potentially facilitate advances in medicine.…”

Recent advances in modeling membrane beta-barrel proteins using molecular dynamics simulations: from their lipid environments to their assemblies

“…Ion conductance of both bacterial channels and pore-forming toxin nanopores was investigated using steric exclusion model and AA-MD simulations [75]. For interested readers, a recent perspective has summarized advances in understanding key issues in molecular simulations of antibiotic translocation and in the development of nanopore sensors [76].…”