Treatment of Ionic Strength in Biomolecular Simulations of Charged Lipid Bilayers

Abstract

Biological membranes are complex systems that have recently attracted a significant scientific interest. Due to the presence of many different anionic lipids, these membranes are usually negatively charged and sensitive to pH. The protonation states of lipids and the ion distribution close to the bilayer are two of the main challenges in biomolecular simulations of these systems. These two problems have been circumvented by using ionized (deprotonated) anionic lipids and enough counterions to preserve the electroneutrality. In this work, we propose a method based on the Poisson-Boltzmann equation to estimate the counterion and co-ion concentration close to a lipid bilayer that avoids the need for neutrality at this microscopic level. The estimated number of ions was tested in molecular dynamics simulations of a 25% DMPA/DMPC lipid bilayer at different ionization levels. Our results show that the system neutralization represents an overestimation of the number of counterions. Consequently, the resulting lipid bilayer becomes too ordered and practically insensitive to ionization. On the other hand, our proposed approach is able to correctly model the ionization dependent isothermal phase transition of the bilayer observed experimentally. Furthermore, our approach is not too computationally expensive and can easily be used to model diverse charged biomolecular systems in molecular dynamics simulations.

Simulation of lipid bilayer self-assembly using all-atom lipid force fields

“…30,68 Lipid14, together with the various AMBER ion parameters, is no exception in that regard. Monovalent counterions described by parameters recently developed by Joung and Cheatham 69 have been found to condense anionic Lipid14 bilayers to areas per lipid well below experimental values (results not shown) due to strong interactions with the negatively charged lipid head groups.…”

pH-Responsive Self-Assembly of Polysaccharide through a Rugged Energy Landscape

“…Titratable water was used to maintain constant charge throughout the simulations for all pH conditions. 24,25 Recent work from other groups showed that the number of counter-ions required to neutralize a simulation box may result in an artificially high concentration of ions near a charged solute, 39 and that high ion concentrations can possibly lead to artifacts. 40 However, since the potential artifacts affect the morphology of lipid and surfactant assemblies, which is not the topic of this work, we feel that the charge neutralization scheme used here is appropriate, especially given that our recent work showed that enforcing charge neutrality in the simulation box significantly improves the accuracy of all-atom constant pH MD simulations.…”

Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study

“…In one of them, we kept the Berger lipids/HF 6-31G(d) probe topologies used in the main set of simulations, but added sodium and chloride ions to a physiological (150 mM) ionic strength. It should be stressed that possibly owing to the relatively small simulation boxes (namely in the direction normal to the bilayer plane) that may be presently addressed in atomistic MD, as well as to uncertainty in the force field parameters of common ions, the number of cations in close vicinity of the bilayer is overestimated in the conventional MD simulation protocols [98][99][100]. In turn, this leads to an overestimation of ion-induced alterations of host lipid properties.…”