Water permeation across artificial I-quartet membrane channels: from structure to disorder

Abstract

Artificial water channels (AWCs) have been designed for water transport across membranes with the aim to mimic the high water permeability observed for biological systems such as aquaporins (∼108-109 water molecules per s per channel), as well as their selectivity to reject ion permeation at the same time. Recent works on designed self-assembling alkylureido-ethylimidazole compounds forming imidazole-quartet channels (I-quartets), have shown both high water permeability and total ionic-rejection. I-quartets are thus promising candidates for further development of AWCs. However, the molecular mechanism of water permeation as well as I-quartet organization and stability in a membrane environment need to be fully understood to guide their optimal design. Here, we use a wide range of all-atom molecular dynamics (MD) simulations and their analysis to understand the structure/activity relationships of the I-quartet channels. Four different types with varying alkyl chain length or chirality have been studied in a complex fully hydrated lipid bilayer environment at both microsecond and nanosecond scale. Microsecond simulations show two distinct behaviors; (i) two out of four systems maintain chiral dipolar oriented water wires, but also undergo a strong reorganization of the crystal shape, (ii) the two other I-quartet channels completely lose the initial organization, nonetheless keeping a water transport activity. Short MD simulations with higher time resolution were conducted to characterize the dynamic properties of water molecules in these model channels and provided a detailed hypothesis on the molecular mechanism of water permeation. The ordered confined water was characterized with quantitative measures of hydrogen-bond life-time and single particle dynamics, showing variability among I-quartet channels. We will further discuss the underlying assumptions, currently based on self-aggregation simulations and crystal patches embedded in lipid bilayer simulations and attempt to describe possible alternative approaches to computationally capture the water permeation mechanism and the self-assembly process of these AWCs.

Water in Nanopores and Biological Channels: A Molecular Simulation Perspective

“…Further MD simulations via two different setup procedures suggest that in addition to ordered water wires through the channels, there may be an alternative disordered mechanism of water transport involving perturbations in the surrounding membrane. 287 …”

Porous organic cages as synthetic water channels

“…This strategy imposes a critical vertical alignment configuration such that exposing the larger channel sides to the salt-rich feed can potentially lower its salt-rejection efficiency. Such alignment issues in unimolecular channels and conformation stability of the self-assembled channels 16 can significantly impede the channel performance. These factors represent a formidable design challenge in synthetic chemistry.…”

Using Computer Simulations and Virtual Reality to Understand, Design and Optimize Artificial Water Channels

“…Important studies of AWCs including molecular dynam ics (MD) simulations have been pioneered by several groups around the world, notably in the USA, China, Singapore, Hong-Kong, etc. Molecular modeling approaches -in particular molecular dynamics in explicit solvent and membrane environments -constitute a pivotal tool to extend the methodology, providing insight at a molecular scale as described in [19][20][21]. Moving up in scales, the development of multi-scale approaches to describe hydrodynamics in molecular systems has the potential to provide new stimulus for water channel modeling [22,23].…”

“…First results may illustrate these ideas. Previous MD simulation studies of dynamic behaviors of the artificial I-quartet water channels and water molecules under confined conditions in a lipid bilayer environment were reported in [19][20][21]. An important aspect to bear in mind from these works is the quantitative correlation be-tween the dipolar orientation of water-wires and their effects on their stability once inserted in the bilayer membranes.…”