Investigation of Finite System-Size Effects in Molecular Dynamics Simulations of Lipid Bilayers

Abstract

In the absence of external stress, the surface tension of a lipid membrane vanishes at equilibrium, and the membrane exhibits long wavelength undulations that can be described as elastic (as opposed to tension-dominated) deformations. These long wavelength fluctuations are generally suppressed in molecular dynamics simulations of membranes, which have typically been carried out on membrane patches with areas <100 nm2 that are replicated by periodic boundary conditions. As a result, finite system-size effects in molecular dynamics simulations of lipid bilayers have been subject to much discussion in the membrane simulation community for several years, and it has been argued that it is necessary to simulate small membrane patches under tension to properly model the tension-free state of macroscopic membranes. Recent hardware and software advances have made it possible to simulate larger, all-atom systems allowing us to directly address the question of whether the relatively small size of current membrane simulations affects their physical characteristics compared to real macroscopic bilayer systems. In this work, system-size effects on the structure of a DOPC bilayer at 5.4 H2O/lipid are investigated by performing molecular dynamics simulations at constant temperature and isotropic pressure (i.e., vanishing surface tension) of small and large single bilayer patches (72 and 288 lipids, respectively), as well as an explicitly multilamellar system consisting of a stack of five 72-lipid bilayers, all replicated in three dimensions by using periodic boundary conditions. The simulation results are compared to X-ray and neutron diffraction data by using a model-free, reciprocal space approach developed recently in our laboratories. Our analysis demonstrates that finite-size effects are negligible in simulations of DOPC bilayers at low hydration, and suggests that refinements are needed in the simulation force fields.

An NMR database for simulations of membrane dynamics

“…Carefully designed hybrid unified-atom simulations targeting membrane properties—as in the case of the frequency-dependent relaxation rates for simple membrane systems—have detected membrane deformations that occur on a length scale larger than the molecular dimensions of the lipid. Given the proper simulation environment the emergence of slow dynamic modes is observed [10,179]. These force-fields retain a coarse-grained character resembling the atomistic simulation, while they enable the simulation to be extended to larger molecular systems and longer timescales through a reduction of the number of atoms considered in the simulation.…”

Molecular basis of endosomal-membrane association for the dengue virus envelope protein

“…These effects have been attributed to the inability of smaller simulations to describe capillary waves. However, a more recent comparison of simulation sizes containing 72 and 288 DOPC lipids (1,2-dioleoyl-sn-glycero-3-phosphocholine) [87] have shown that finite size effects are negligible for these larger system sizes. This conclusion agrees with thorough studies of the relationship between surface tension and capillary waves at the water/ vapor interface [88], which showed a small, but statistically insignificant increase in tension with simulation area.…”

Recent development in computer simulations of lipid bilayers

“…Finite system-size effects in MD simulations of lipid bilayers are subject to much discussion in the membrane simulation community. In work 82 , system-size effects on the structure of a 18:1(n-9)cis/18:1(n-9)cis PC bilayer are investigated by performing MD simulations of small and large single bilayer patches (72 and 288 lipids, respectively), as well as an explicitly multilamellar system consisting of a stack of five 72-lipid bilayers, all replicated in three dimensions by using periodic boundary conditions. The analysis 82 demonstrates that finite-size effects are negligible in simulations of 18:1(n-9)cis/18:1(n-9)cis PC bilayers at low hydration.…”

“…In work 82 , system-size effects on the structure of a 18:1(n-9)cis/18:1(n-9)cis PC bilayer are investigated by performing MD simulations of small and large single bilayer patches (72 and 288 lipids, respectively), as well as an explicitly multilamellar system consisting of a stack of five 72-lipid bilayers, all replicated in three dimensions by using periodic boundary conditions. The analysis 82 demonstrates that finite-size effects are negligible in simulations of 18:1(n-9)cis/18:1(n-9)cis PC bilayers at low hydration. A similar study was performed for a saturated bilayer: MD simulations of 16:0/16:0 PC bilayers composed of 72 and 288 lipids were used in 83 to examine system size dependence on dynamical properties.…”