Dataset Information

The effect of sterols on amphotericin B self-aggregation in a lipid bilayer as revealed by free energy simulations.

ABSTRACT: Amphotericin B (AmB) is an effective but toxic antifungal drug, known to increase the permeability of the cell membrane, presumably by assembling into transmembrane pores in a sterol-dependent manner. The aggregation of AmB molecules in a phospholipid bilayer is, thus, crucial for the drug's activity. To provide an insight into the molecular nature of this process, here, we report an atomistic molecular dynamics simulation study of AmB head-to-head dimerization in a phospholipid bilayer, a possible early stage of aggregation. To compare the effect of sterols on the thermodynamics of aggregation and the architecture of the resulting AmB-AmB complexes, free energy profiles for the dimerization in ergosterol- or cholesterol-containing and sterol-free membranes are derived from the simulations. These profiles demonstrate that although AmB dimers are formed in all the systems studied, they are significantly less favorable in the bilayer with ergosterol than in the cholesterol-containing or sterol-free ones. We investigate the structural and energetic determinants of this difference and discuss its consequences for the AmB mechanism of action.

SUBMITTER: Neumann A

PROVIDER: S-EPMC3617414 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The effect of sterols on amphotericin B self-aggregation in a lipid bilayer as revealed by free energy simulations.

Neumann Anna A Baginski Maciej M Winczewski Szymon S Czub Jacek J

Biophysical journal 20130401 7

Amphotericin B (AmB) is an effective but toxic antifungal drug, known to increase the permeability of the cell membrane, presumably by assembling into transmembrane pores in a sterol-dependent manner. The aggregation of AmB molecules in a phospholipid bilayer is, thus, crucial for the drug's activity. To provide an insight into the molecular nature of this process, here, we report an atomistic molecular dynamics simulation study of AmB head-to-head dimerization in a phospholipid bilayer, a possi ...[more]

PMID: 23561525

Similar Datasets

Project description:Molecular dynamics (MD) simulations have become an indispensable tool to investigate phase separation in model membrane systems. In particular, simulations based on coarse-grained (CG) models have found widespread use due to their increased computational efficiency, allowing for simulations of multicomponent lipid bilayers undergoing phase separation into liquid-ordered and liquid-disordered domains. Here, we show that a significant temperature difference between molecule types can artificially arise in CG MD membrane simulations with the standard Martini simulation parameters in GROMACS. In particular, the linear constraint solver (LINCS) algorithm does not converge with its default settings, resulting in serious temperature differences between molecules in a time step-dependent manner. We demonstrate that the underlying reason for this behavior is the presence of highly constrained moieties, such as cholesterol. Their presence can critically impact numerous structural and dynamic membrane properties obtained from such simulations. Furthermore, any preference of these molecules toward a certain membrane phase can lead to spatial temperature gradients, which can amplify the degree of phase separation or even induce it in compositions that would otherwise mix well. We systematically investigated the effect of the integration time step and LINCS settings on membrane properties. Our data show that for cholesterol-containing membranes, a time step of 20 fs should be combined with at least lincs_iter = 2 and lincs_order = 12, while using a time step of 30 fs requires at least lincs_iter = 3 and lincs_order = 12 to bring the temperature differences to a level where they do not perturb central membrane properties. Moreover, we show that in cases where stricter LINCS settings are computationally too demanding, coupling the lipids in multiple groups to the temperature bath offers a practical workaround to the problem, although the validity of this approach should be further verified. Finally, we show that similar temperature gradients can also emerge in atomistic simulations using the CHARMM force field in combination with settings that allow for a 5 fs integration step.

Dataset Information

The effect of sterols on amphotericin B self-aggregation in a lipid bilayer as revealed by free energy simulations.

Publications

The effect of sterols on amphotericin B self-aggregation in a lipid bilayer as revealed by free energy simulations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets