Review
Dynamic processes in biological membrane mimics revealed by quasielastic neutron scattering

https://doi.org/10.1016/j.chemphyslip.2017.05.009Get rights and content

Highlights

Abstract

Neutron scattering is a powerful tool to study relaxation processes in biological membrane mimics in space and time. Combining different inelastic and quasielastic neutron scattering techniques, a large dynamic range can be covered: from atomic to mesoscopic lengths and from femto- to some hundreds of nanoseconds in time. This allows studies on e.g. the diffusion of lipids, the membrane undulation motions, the dispersion of sound waves in membranes as well as the mutual interactions of membrane constituents such as lipids, proteins, and additives.

In particular, neutron scattering provides a quite direct experimental approach to the inter-atomic and inter-molecular potentials on length and time scales which are perfectly accessible by molecular dynamics (MD) simulations. Neutron scattering experiments may thus substantially support the further refinement of biomolecular force fields for MD simulations by supplying structural and dynamical information with high spatial and temporal resolution. In turn, MD simulations support the interpretation of neutron scattering data. The combination of both, neutron scattering experiments and MD simulations, yields an unprecedented insight into the molecular interactions governing the structure and dynamics of biological membranes.

This review provides an overview of the molecular dynamics in biological membrane mimics as revealed by neutron scattering. It focuses on the latest findings such as the fundamental molecular mechanism of lateral lipid diffusion as well as the influence of additives and proteins on the short-time dynamics of lipids. Special emphasis is placed on the comparison of recent neutron scattering and MD simulation data with respect to molecular membrane dynamics on the pico- to nanosecond time scale.

Introduction

Knowledge concerning the organization of biological cell membranes as well as their structure and dynamics is highly important for the fields of biology and biophysics, but also for pharmaceutical applications (Peetla et al., 2009) or the food industry (Sagalowicz and Leser, 2010). As complex systems, biological membranes are mainly composed of different types of lipids, membrane-embedded or -adhered proteins and sterols. Most of the cellular functions, as e.g. signal or molecular transport, are influenced by composition, lateral organization, and dynamics of the membrane. I.e. the activity of many membrane proteins was shown to depend critically on the membrane composition.

In 1972, Singer and Nicolson (1972) demonstrated the importance of research on membrane composition, structure and organization in order to obtain an in-depth understanding of different cellular phenomena. The authors developed a model which characterizes the membrane as a two-dimensional fluid mosaic structure (fluid mosaic model) consisting of a lipid bilayer matrix wherein the proteins are embedded (cf. Fig. 1). In this model, the lipids and proteins are assumed to diffuse almost freely in the plane of the membrane.

Small angle X-ray and neutron scattering (SAXS, SANS) but also X-ray and neutron reflectivity (XRR, NR) experiments are well suited to study the molecular structure of biological membranes in detail. The combination with molecular dynamics (MD) simulations yields information about structural properties of membranes (Kučerka et al., 2015), e.g. the thickness of lipid bilayers (Kučerka et al., 2004), the asymmetric distribution of certain lipids (Hirai et al., 2003), the effect of cholesterol (Kučerka et al., 2009), the effect of adding drugs such as ibuprofen (Boggara et al., 2010, Jaksch et al., 2015), the size of domains (Heberle et al., 2013), the coexistence of gel and fluid lipid domains (Armstrong et al., 2012) and many more (Fitter et al., 2006, Pabst et al., 2010).

The dynamics of membrane components and their mobility within the membrane are essential for various cellular functions. Scattering techniques with cold and thermal neutrons provide the outstanding advantage to probe complex membrane systems in-situ without using any label (as e.g. fluorescence labels) and do not cause notable radiation damage. They enable access to both, atomic self- and collective dynamics on pico- to nanosecond time scales and nanometer length scales. As neutron instrumentation develops continuously, the experimental capabilities increased significantly in the last decade, as exemplary demonstrated for time-of-flight spectroscopy by the TOFTOF spectrometer at the Heinz Maier-Leibnitz Zentrum (MLZ, Garching, Germany) (Unruh et al., 2007) or the IN5 spectrometer at the Institut Laue-Langevin (ILL, Grenoble, France) (Ollivier et al., 2010) as well as for backscattering spectroscopy by the IN16B spectrometer at ILL (Frick et al., 2010). It is therefore not surprising that neutron scattering techniques are used for quite some time to study the dynamics of membrane mimics (García Sakai and Arbe, 2009) and become more and more important due to the increasing experimental capabilities. These membrane mimics were composed of lipid bilayers with only one type of lipid (Salditt, 2000; König et al., 1992), a mixture of different lipids (Bloom and Bayerl, 1995), or even more complex by adding cholesterol and other additives (Busch and Unruh, 2011, Endress et al., 2002, Yi et al., 2012, Armstrong et al., 2014) or proteins (Buchsteiner et al., 2010, Sharma et al., 2015) to the lipid bilayer. Neutron scattering experiments were performed on e.g. liquid-crystalline multilayers (Busch et al., 2010, Busch and Unruh, 2011), vesicles (Sharma et al., 2015, Busch et al., 2012), or multilayer stacks on a solid support as e.g. on silicon wafers (Gliss et al., 1999, Armstrong et al., 2010).

An experimental access to the structure and function of biomembranes becomes more and more challenging with growing complexity of the membrane composition (lipids, proteins, and sterols). In this context, MD simulations have proven to be a valuable method complementary to neutron scattering for understanding complex biological systems in more detail (Hansen et al., 2012, Toppozini et al., 2015, Bai et al., 2012, Watson et al., 2011, Brandt and Edholm, 2010, Benedetto et al., 2015, Ollila and Pabst, 2016) and also for revealing structural parameters of lipid membranes (Kučerka et al., 2015). On the one hand, realistic models of lipid bilayers derived from MD simulations were used to convert experimental structure factors to electron densities (Kučerka et al., 2010; Holland et al., 2014). On the other hand, the comparison of structure factors allows to control the predictive nature of MD simulations (Pluhackova et al., 2016) and thereby expedite the further development of force field parameters (Klauda et al., 2010; Jämbeck and Lyubartsev, 2012; Dickson et al., 2014). This combined approach proved to be useful not only in studies of pure bilayers, but also in order to determine the effects of additives (like cholesterol or melatonin) on the membrane structure (Drolle et al., 2013).

Nevertheless, so far, there are almost no simultaneous MD simulations and neutron scattering studies probing the pico- to nanosecond dynamics of biological membranes. Since the last review articles by García Sakai and Arbe (2009) and Pabst et al. (2010), new insight into the molecular structure and dynamics of biological membranes could be acquired. Recently, Metzler et al. (2016) published a review about non-Brownian diffusion in membranes and the advantage to combine single particle tracking experiments with MD simulations to understand the mechanism in complex biological systems. Therefore, this review will mainly focus on the latest findings concerning fundamental molecular mechanism of lipid dynamics and the influence of additives and peptides on the short-time dynamics of membranes revealed by quasielastic neutron scattering (QENS). Additionally, it aims to outline the value of combining neutron scattering data with MD simulations to obtain a more detailed understanding of the molecular mechanism in complex biological systems. For that reason, some new results of a recent study of the authors combining QENS experiments and MD simulations are presented as well.

Section snippets

Quasielastic neutron scattering

QENS techniques such as time-of-flight, backscattering or spin echo spectroscopy give access to atomic and molecular relaxation processes on time scales from sub-picoseconds to hundreds of nanoseconds and length scales from a few Ångstrøms to several hundred nanometers (Bee, 1988) at which many important biological processes such as signal transduction or metabolite transport take place (García Sakai et al., 2012).

Relaxation processes such as diffusion or rotation of atoms, molecules or

Fundamental molecular mechanism of membrane dynamics

Some amphiphilic lipid molecules tend to form bilayers in water or oil depending on their packing parameter p=volumearea·length (Domb et al., 1994). These bilayers build up the matrix of biological membranes. In QENS experiments these lipid molecules were often used to mimic biological membranes and to study different lipid motions (Pabst et al., 2010, König et al., 1992, Bloom and Bayerl, 1995, Rheinstädter et al., 2004, Rheinstädter et al., 2005, Rheinstädter et al., 2006, Pfeiffer et al.,

Interactions between lipids and proteins

Proteins, involved in various cellular functions, are along with lipids crucial components of biological membranes. Recently, several QENS studies were performed to reveal lipid-protein interactions on atomistic length and time scales (Vogel et al., 2012, Knoll et al., 2014).

The Alzheimer peptide, amyloid-β, is known to be the main component of senile plaques which are believed to cause Alzheimer's disease (Hardy and Selkoe, 2002). Therefore, amyloid-β attracts great interest of researchers who

Influence of additives on lipid dynamics

In the studies of artificial membranes the trend towards more complex systems to mimic biological membranes is clearly visible. Besides varying and extending the lipid composition of the membrane, different additives (e.g. sterols) are often added to the lipids. In this way the influence of the different additives on the dynamics of membranes can be studied which is important for a detailed understanding of membrane functionalities (Gerelli et al., 2011; Brüning and Farago, 2014). The sterol

Lipid dynamics revealed by QENS and MD simulations

The combination of quasielastic neutron scattering experiments and MD simulations is widely used to investigate the membrane structure and dynamics in detail (Vural et al., 2017). QENS detects lipid dynamics on the sub-pico- to nanosecond time range and is thus complementary to e.g. pulsed field gradient nuclear magnetic resonance (PFG-NMR) studies which probe the molecular motions on rather long time scales (μs to s). Furthermore, QENS allows to associate dynamical processes directly with a

Conclusion

In this review, we summarized the latest findings on the dynamics of biological membrane mimics studied by quasielastic neutron scattering (QENS). Some aspects of the combination of QENS studies and molecular dynamics (MD) simulations are addressed as well. Significant development was achieved during the past years in understanding the fundamental molecular interactions and dynamics of lipids (internal molecular motions and long-range motions) and of pure lipid membranes. Additionally, the

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Transparency document

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Acknowledgments

We acknowledge support by the Research Training Group 1962/1, Dynamic Interactions at Biological Membranes – from Single Molecules to Tissue and by the Cluster of Excellence Engineering of Advanced Materials, both funded by the Deutsche Forschungsgemeinschaft (DFG).

References (124)

  • V. García Sakai et al.

    Dynamics of Soft Matter: Neutron Applications

    (2012)
  • F.Y. Hansen et al.

    Diffusion of water and selected atoms in DMPC lipid bilayer membranes

    J. Chem. Phys.

    (2012)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)
  • F.A. Heberle et al.

    Bilayer thickness mismatch controls domain size in model membranes

    J. Am. Chem. Soc.

    (2013)
  • B.W. Holland et al.

    SIMtoEXP: software for comparing simulations to experimental scattering data

    Biophys. J.

    (2014)
  • J.P.M. Jämbeck et al.

    Derivation and systematic validation of a refined all-atom force field for phosphatidylcholine lipids

    J. Phys. Chem. B

    (2012)
  • S. Jaksch et al.

    Influence of ibuprofen on phospholipid membranes

    Phys. Rev. E

    (2015)
  • M. Javanainen et al.

    Anomalous and normal diffusion of proteins and lipids in crowded lipid membranes

    Faraday Discuss.

    (2013)
  • J.B. Klauda et al.

    Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types

    J. Phys. Chem. B

    (2010)
  • N. Kučerka et al.

    Asymmetric distribution of cholesterol in unilamellar vesicles of monounsaturated phospholipids

    Langmuir

    (2009)
  • H. Morhenn et al.

    Collective intermolecular motions dominate the picosecond dynamics of short polymer chains

    Phys. Rev. Lett.

    (2013)
  • G. Pabst et al.

    Applications of neutron and X-ray scattering to the study of biologically relevant model membranes

    Chem. Phys. Lipids

    (2010)
  • M. Patra et al.

    Under the influence of alcohol: the effect of ethanol and methanol on lipid bilayers

    Biophys. J.

    (2006)
  • C. Peetla et al.

    Biophysical interactions with model lipid membranes: applications in drug discovery and drug delivery

    Mol. Pharm.

    (2009)
  • W. Pfeiffer et al.

    Local dynamics of lipid bilayers studied by incoherent quasi-elastic neutron scattering

    Europhys. Lett.

    (1989)
  • W. Pfeiffer et al.

    Neutron spin echo study of membrane undulations in lipid multibilayers

    Europhys. Lett.

    (1993)
  • P.F.F. Almeida et al.

    Lateral diffusion in the liquid phases of dimyristoylphosphatidylcholine/cholesterol lipid bilayers: a free volume analysis

    Biochemistry

    (1992)
  • B. Aoun et al.

    Structure and dynamics of ionic micelles: MD simulation and neutron scattering study

    J. Phys. Chem. B

    (2015)
  • C.L. Armstrong et al.

    Diffusion in single supported lipid bilayers studied by quasi-elastic neutron scattering

    Soft Matter

    (2010)
  • C.L. Armstrong et al.

    Short range ballistic motion in fluid lipid bilayers studied by quasi-elastic neutron scattering

    Soft Matter

    (2011)
  • C.L. Armstrong et al.

    Effect of cholesterol an the lateral nanoscale dynamics of fluid membranes

    Eur. Biophys. J.

    (2012)
    C.L. Armstrong et al.

    Co-existence of gel and fluid lipid domains in single-component phospholipid membranes

    Soft Matter

    (2012)
  • C.L. Armstrong et al.

    Nanosecond lipid dynamics in membranes containing cholesterol

    Soft Matter

    (2014)
  • R.A. Böckmann et al.

    Effect of sodium chloride on a lipid bilayer

    Biophys. J.

    (2003)
  • M.A. Barrett et al.

    Alzheimer's peptide amyloid-β, fragment 22–40, perturbs lipid dynamics

    Soft Matter

    (2016)
  • M. Bee

    Quasielastic Neutron Scattering

    (1988)
  • A. Benedetto et al.

    Structure and dynamics of POPC bilayers in water solutions of room temperature ionic liquids

    J. Chem. Phys.

    (2015)
  • H.J.C. Berendsen et al.

    Interaction models for water in relation to protein hydration

    Intermol. Forces

    (1981)
  • M. Bloom et al.

    Membranes studied using neutron scattering and NMR

    Can. J. Phys.

    (1995)
  • M.B. Boggara et al.

    Effect of pH and ibuprofen on the phospholipid bilayer bending modulus

    J. Phys. Chem. B

    (2010)
  • B. Brüning et al.

    Perfluorooctanoic acid rigidifies a model lipid membrane

    Phys. Rev. E

    (2014)
  • B.-A. Brüning et al.

    Bilayer undulation dynamics in unilamellar phospholipid vesicles: Effect of temperature, cholesterol and trehalose

    Biochim. Biophys. Acta

    (2014)
  • A. Buchsteiner et al.

    Alzheimer's disease amyloid-β peptide analogue alters the ps-dynamics of phospholipid membranes

    Biochim. Biophys. Acta

    (2010)
  • A. Buchsteiner et al.

    Influence of amyloid-β peptides with different lengths and amino acid sequences on the lateral diffusion of lipids in model membranes

    Soft Matter

    (2012)
  • S. Busch et al.

    Molecular mechanism of long-range diffusion in phospholipid membranes studied by quasielastic neutron scattering

    J. Am. Chem. Soc.

    (2010)
  • S. Busch

    The Pico- to Nanosecond Dynamics of Phospholipid Molecules

    (2012)
  • V. Calandrini et al.

    nMOLDYN: User's Guide

    (2006)
  • C. Cevc

    Phospholipids Handbook

    (1993)
  • A.N. Dickey et al.

    How alcohol chain-length and concentration modulate hydrogen bond formation in a lipid bilayer

    Biophys. J.

    (2007)
  • C.J. Dickson et al.

    Lipid14: the amber lipid force field

    J. Chem. Theory Comput.

    (2014)
  • C. Domb et al.

    Self-Assembling Amphiphilic Systems (Phase Transitions and Critical Phenomena)

    (1994)
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