Exploring transmembrane transport through α-hemolysin with grid-steered molecular dynamics

Abstract

The transport of biomolecules across cell boundaries is central to cellular function. While structures of many membrane channels are known, the permeation mechanism is known only for a select few. Molecular dynamics (MD) is a computational method that can provide an accurate description of permeation events at the atomic level, which is required for understanding the transport mechanism. However, due to the relatively short time scales accessible to this method, it is of limited utility. Here, we present a method for all-atom simulation of electric field-driven transport of large solutes through membrane channels, which in tens of nanoseconds can provide a realistic account of a permeation event that would require a millisecond simulation using conventional MD. In this method, the average distribution of the electrostatic potential in a membrane channel under a transmembrane bias of interest is determined first from an all-atom MD simulation. This electrostatic potential, defined on a grid, is subsequently applied to a charged solute to steer its permeation through the membrane channel. We apply this method to investigate permeation of DNA strands, DNA hairpins, and alpha-helical peptides through alpha-hemolysin. To test the accuracy of the method, we computed the relative permeation rates of DNA strands having different sequences and global orientations. The results of the G-SMD simulations were found to be in good agreement in experiment.

A Statistical Model for Translocation of Structured Polypeptide Chains through Nanopores

“…This approach reveals to be particularly suitable to describe the properties of processes characterized by a low degree of chemical details, such as translocation of unstructured biopolymers or homopolymers. [17][18][19] Simulations at atomic resolution [20][21][22] of both proteins and membrane pores, although very informative on molecular details, explore time scales too short with respect to real translocation times.…”

Dendrimers in Nanoscale Confinement: The Interplay between Conformational Change and Nanopore Entrance

“…50 In this approach, an electrostatic grid potential obtained at low voltages is scaled up to accelerate the molecular movement to times scales accessible to simulations while reducing artificial distortions in molecular configurations. 50 GSMD has been Nano Lett. XXXX, XXX, XXX−XXX successfully applied to simulate the translocation of DNA strands, DNA hairpins and α-helical peptides through αHL.…”

Modeling the Interface between Biological and SyntheticComponents in Hybrid Nanosystems

“…To prevent atoms from evaporating into the vacuum region, external forces were applied with grid-steered molecular dynamics [153]. The resulting amorphous silica slab was tiled in a two-by-two grid to create a 5.0 x 5.0 x 2.6 nm 3 silica membrane with two exposed faces consisting of four identical patches of silica.…”

“…This surface did not consist of atoms; instead an infinitely smooth, frictionless surface was modeled by applying the following smooth potential to all atoms using G-SMD [153]. …”

“…A smooth (1.0-1.2 nm) cutoff was used to compute the van der Waals forces. External potentials were applied using grid-steered molecular dynamics (G-SMD) [153]. The nanochannel simulations were performed using the CHARMM [44] force field for water, ions and proteins and a custom forcefield for silica [49].…”