Effect of Water Models on Transmembrane Self-Assembled Cyclic Peptide Nanotubes.

Martin Calvelo,Mark S P Sansom,Rebeca Garcia-Fandiño,Charlotte I Lynch,Juan R Granja

doi:10.1021/acsnano.1c00155

Martin Calvelo, Mark S P Sansom + Show 3 more

Open Access

https://doi.org/10.1021/acsnano.1c00155

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Abstract

Self-assembling cyclic peptide nanotubes can form nanopores when they are inserted in lipid bilayers, acting as ion and/or water permeable channels. In order to improve the versatility of these systems, it is possible to specifically design cyclic peptides with a combination of natural and non-natural amino acids, enabling the control of the nature of the inner cavity of the channels. Here, the behavior of two types of self-assembling peptide motifs, alternating α-amino acids with γ- or δ-aminocycloalkanecarboxylic acids, is studied via molecular dynamics (MD) simulations. The behavior of water molecules in nanopores is expected to affect the properties of these channels and therefore merits detailed examination. A number of water models commonly used in MD simulations have been validated by how well they reproduce bulk water properties. However, it is less clear how these water models behave in the nanoconfined condition inside a channel. The behavior of four different water models—TIP3P, TIP4P, TIP4P/2005, and OPC—are evaluated in MD simulations of self-assembled cyclic peptide nanotubes of distinct composition and diameter. The dynamic behavior of the water molecules and ions in these designed artificial channels depends subtly on the water model used. TIP3P water molecules move faster than those of TIP4P, TIP4P/2005, and OPC. This demeanor is clearly observed in the filling of the nanotube, in water diffusion within the pore, and in the number and stability of hydrogen bonds of the peptides with water. It was also shown that the water model influences the simulated ion flux through the nanotubes, with TIP3P producing the greatest ion flux. Additionally, the two more recent models, TIP4P/2005 and OPC, which are known to reproduce the experimental self-diffusion coefficient of bulk water quite well, exhibit very similar results under the nanoconfined conditions studied here. Because none of these models have been parametrized specifically for waters confined in peptide nanotubes, this study provides a point of reference for further validation.

Highlights

Self-assembling cyclic peptide nanotubes can form nanopores when they are inserted in lipid bilayers, acting as ion and/or water permeable channels
In this study we describe in detail the structural stability of two kinds of Self-assembled cyclic peptide nanotubes (SCPNs) inserted into a phospholipid bilayer, α,γSCPNs and α,δ-SCPNs (Figure 1B,C), alongside simulation of their interactions with four water models, two of which (TIP3P and TIP4P) have been used in many studies of biomolecules and nanopores, as well as two more recently developed water models (TIP4P/2005 and OPC).[66−69] Whereas the α,γ-SCPN is composed of eight residue-long CPs, the α,δ-CPs of the latter SCPN contain 12 amino acid residues (6 α-Aa and 6 δaminocyclohexanecarboxylic acid)
A systematic molecular dynamics simulation study comparing the behavior of four water models (TIP3P, TIP4P, TIP4P/ 2005, and OPC) inside two sizes of self-assembled cyclic peptide nanotubes (α,γ-SCPN and α,δ-SCPNs) has been carried out

Summary

Introduction

Self-assembling cyclic peptide nanotubes can form nanopores when they are inserted in lipid bilayers, acting as ion and/or water permeable channels. To date, the best practice for MD simulations involving water in confined systems is to compare results obtained with different water models

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