Molecular dynamics simulations of membrane proteins under asymmetric ionic concentrations

Abstract

A computational method is developed to allow molecular dynamics simulations of biomembrane systems under realistic ionic gradients and asymmetric salt concentrations while maintaining the conventional periodic boundary conditions required to minimize finite-size effects in an all-atom explicit solvent representation. The method, which consists of introducing a nonperiodic energy step acting on the ionic species at the edge of the simulation cell, is first tested with illustrative applications to a simple membrane slab model and a phospholipid membrane bilayer. The nonperiodic energy-step method is then used to calculate the reversal potential of the bacterial porin OmpF, a large cation-specific β-barrel channel, by simulating the I-V curve under an asymmetric 10:1 KCl concentration gradient. The calculated reversal potential of 28.6 mV is found to be in excellent agreement with the values of 26–27 mV measured from lipid bilayer experiments, thereby demonstrating that the method allows realistic simulations of nonequilibrium membrane transport with quantitative accuracy. As a final example, the pore domain of Kv1.2, a highly selective voltage-activated K+ channel, is simulated in a lipid bilayer under conditions that recreate, for the first time, the physiological K+ and Na+ concentration gradients and the electrostatic potential difference of living cells.

Exploring the Membrane Potential of Simple Dual-Membrane Systems as Models for Gap-Junction Channels

“…While the former property is related to asymmetries in charge distributions within the channel, the latter depends on conformational changes promoted by the existence of a transmembrane potential difference (13). Numerous studies based on MD simulations of single-membrane ion channels have characterized the effect of transmembrane potential (3)(4)(5)(6). However, to our knowledge, no studies have been focused on the effects of the intrinsic (pore-lining) charge density under voltage differences on dual-membrane molecular systems.…”

“…This heterogeneity of charge distribution is produced by the action of ionic pumps and ion channels (1), generating an electrochemical gradient, i.e., a voltage difference, which is crucial to regulate a variety of intercellular communication processes such as the regulation of cell homeostasis and the conduction of the neuron action potential (2). In the case of single-membrane systems, voltage-dependent modulation of ionic transport via structural rearrangements of ion channels is well understood, being extensively described by several groups with atomistic resolution (3)(4)(5)(6). It depends on the presence of charged residues that will react under the influence of an external electrostatic potential, generating conformational changes to allow or disrupt the passage of ionic species through the channels.…”

“…Notwithstanding the fact that all-atom simulation approaches of similar macromolecular assemblies have been carried out (20,21), the understanding of the underlying mechanisms governing the behavior of these complex and large structures requires the development of simpler (and less computational demanding) model systems to evaluate working hypotheses. Following this approach, previous studies have shown that the basic features of voltage effects are preserved when employing simple pore models in molecular dynamics (MD) simulations, permitting an atomistic description of transport and structural properties, resulting voltages and thermodynamics (4,(22)(23)(24)(25).…”

Computational modeling of membrane proteins

“…However, studying the molecular mechanism of protein folding, membrane partitioning, or specific protein interactions (e.g., drug‐protein or protein‐lipid) requires atomic detail representation of hydrogen bonds. For instance, atomic detail interactions were crucial to uncover the mechanisms of selectivity, ion conduction, and gating of potassium and sodium channels, the voltage‐dependent anion channel, as well as an OMP …”

“…For instance, atomic detail interactions were crucial to uncover the mechanisms of selectivity, ion conduction, and gating of potassium 188,221,222 and sodium channels, 223 the voltage-dependent anion channel, 224 as well as an OMP. 190,225 Which force field and software to use?…”