Dataset Information

Quantitative Characterization of Protein-Lipid Interactions by Free Energy Simulation between Binary Bilayers.

ABSTRACT: Using a recently developed binary bilayer system (BBS) consisting of two patches of laterally contacting bilayers, umbrella sampling molecular dynamics (MD) simulations were performed for quantitative characterization of protein-lipid interactions. The BBS is composed of 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) with an embedded model membrane protein, a gramicidin A (gA) channel. The calculated free energy difference for the transfer of a gA channel from DLPC (hydrophobic thickness ? 21.5 Å) to DMPC (hydrophobic thickness ? 25.5 Å) bilayers, ?G(DLPC ? DMPC), is -2.2 ± 0.7 kcal/mol. This value appears at odds with the traditional view that the hydrophobic length of the gA channel is ?22 Å. To understand this discrepancy, we first note that recent MD simulations by different groups have shown that lipid bilayer thickness profiles in the vicinity of a gA channel differ qualitatively from the deformation profile predicted from continuum elastic bilayer models. Our MD simulations at low and high gA:lipid molar ratios and different membrane compositions indicate that the gA channel's effective hydrophobic length is ?26 Å. Using this effective hydrophobic length, ?G(DLPC ? DMPC) determined here is in excellent agreement with predictions based on continuum elastic models (-3.0 to -2.2 kcal/mol) where the bilayer deformation energy is approximated as a harmonic function of the mismatch between the channel's effective hydrophobic length and the hydrophobic thickness of the bilayer. The free energy profile for gA in the BBS includes a barrier at the interface between the two bilayers which can be attributed to the line tension at the interface between two bilayers with different hydrophobic thicknesses. This observation implies that translation of a peptide between two different regions of a cell membrane (such as between the liquid ordered and disordered phases) may include effects of a barrier at the interface in addition to the relative free energies of the species far from the interface. The BBS allows for direct transfer free energy calculations between bilayers without a need of a reference medium, such as bulk water, and thus provides an efficient simulation protocol for the quantitative characterization of protein-lipid interactions at all-atom resolution.

SUBMITTER: Park S

PROVIDER: S-EPMC7076909 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Quantitative Characterization of Protein-Lipid Interactions by Free Energy Simulation between Binary Bilayers.

Park Soohyung S Yeom Min Sun MS Andersen Olaf S OS Pastor Richard W RW Im Wonpil W

Journal of chemical theory and computation 20191014 11

Using a recently developed binary bilayer system (BBS) consisting of two patches of laterally contacting bilayers, umbrella sampling molecular dynamics (MD) simulations were performed for quantitative characterization of protein-lipid interactions. The BBS is composed of 1,2-dilauroyl-<i>sn</i>-glycero-3-phosphocholine (DLPC) and 1,2-dimyristoyl-<i>sn</i>-glycero-3-phosphocholine (DMPC) with an embedded model membrane protein, a gramicidin A (gA) channel. The calculated free energy difference fo ...[more]

PMID: 31560853

Similar Datasets

Project description:Liquid-liquid phase separation (LLPS) inside the cell often results in biological condensates that can critically impact cell homeostasis. Such phase separation events occur in multiple parts of cells, including the cell membranes, where the so-called "lipid raft" hypothesis posits the formation of ordered domains floating in a sea of disordered lipids. The resulting lipid domains often have functional roles. However, the thermodynamics of lipid phase separation and their resulting mechanistic effects on cell function and dysfunction are poorly understood. Understanding such complex phenomena in cell membranes, with their diverse lipid compositions, is exceptionally difficult. For this reasons, simple model systems that can recapitulate similar behavior are widely used to study this phenomenon. Despite these simplifications, the timescale and and length scales of domain formation pose a challenge for molecular dynamics (MD) simulations. Thus, most MD studies focus on spontaneous lipid phase separation - essentially measuring the sign (but not the amplitude) of the free energy change upon separation - rather than directly interrogating the thermodynamics. Here, we propose a proof-of-concept pipeline that can directly measure this free energy by combining coarse-grained MD with enhanced sampling protocols using a novel collective variable. This approach will be a useful tool to help connect the thermodynamics of phase separation with the mechanistic insights already available from molecular dynamics simulations.SignificanceStandard molecular dynamics simulations can determine the sign the free energy change upon phase separation, but not the amplitude. We present a new method to determine the phase separation free energy for lipid membranes, based on a enhanced sampling using the weighted ensemble method combined with a novel collective variable, validated using coarse-grained simulations applied to several simple systems. The new method will be valuable as a way to develop models that connect molecular-level structural features to the thermodynamics of phase separation.

Dataset Information

Quantitative Characterization of Protein-Lipid Interactions by Free Energy Simulation between Binary Bilayers.

Publications

Quantitative Characterization of Protein-Lipid Interactions by Free Energy Simulation between Binary Bilayers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets