Author Index

Recent studies showed that nanosecond pulsed electric fields (nsPEFs) can activate voltage-gated ion channels (VGICs) and trigger action potentials (APs) in excitable cells. Under physiological conditions, VGICs' activation takes place on time scales of the order 10-100 µs. These time scales are considerably longer than the applied pulse duration, thus activation of VGICs by nsPEFs remains puzzling and there is no clear consensus on the mechanisms involved. Here we propose that changes in local electrical properties of the cell membrane due to lipid oxidation might be implicated in AP activation. We first use MD simulations of model lipid bilayers with increasing concentration of primary and secondary lipid oxidation products and demonstrate that oxidation not only increases the bilayer conductance, but also the bilayer capacitance. Equipped with MD-based characterization of electrical properties of oxidized bilayers, we then resort to AP modelling at the cell level with Hodgkin-Huxley-type models. We confirm that a local change in membrane properties, particularly the increase in membrane conductance, due to formation of oxidized membrane lesions can be high enough to trigger an AP, even when no external stimulus is applied. However, excessive accumulation of oxidized lesions (or other conductive defects) can lead to altered cell excitability.

Nanosecond

Cell membrane

10.1016/j.bioelechem.2023.108588

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Citations (6)

The Local Mechanical Properties of Lipid Bilayers are Altered by Amyloid-Forming Proteins

Biophysical Journal (2013)

Justin Legleiter Kathleen A. Burke Elizabeth A. Yates

Amyloid (mycology)

Lipid bilayer mechanics

10.1016/j.bpj.2012.11.2001

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Citations (0)

Structural characterization of the molten globule of α‐lactalbumin by solution X‐ray scattering

Protein Science (1997)

Mikio Kataoka Fumio Tokunaga Kunihiro Kuwajima Yuji Goto

Abstract A compact denatured state is often observed under a mild denaturation condition for various proteins. A typical example is the α‐lactalbumin molten globule. Although the molecular compactness and shape are the essential properties for defining the molten globule, there have been ambiguities of these properties for the molten globule of α‐lactalbumin. Using solution X‐ray scattering, we have examined the structural properties of two types of molten globule of α‐lactalbumin, the apo‐protein at neutral pH and the acid molten globule. The radius of gyration for the native holo‐protein was 15.7 Å, but the two different molten globules both had a radius of gyration of 17.2 Å. The maximum dimension of the molecule was also increased from 50 Å for the native state to 60 Å for the molten globule. These values clearly indicate that the molten globule is not as compact as the native state. The increment in the radius of gyration was less than 10% for the α‐lactalbumin molten globule, compared with up to 30% for the molten globules of other globular proteins. Intramolecular disulfide bonds restrict the molecular expansion of the molten globule. The distance distribution function of the α‐lactalbumin molten globule is composed of a single peak suggesting a globular shape, which is simply swollen from the native state. The scattering profile in the high Q region of the molten globule indicates the presence of a significant amount of tertiary fold. Based on the structural properties obtained by solution X‐ray scattering, general and conceptual structural images for the molten globules of various proteins are described and compared with the individual, detailed structural model obtained by nuclear magnetic resonance.

Molten globule

Radius of gyration

Globular protein

10.1002/pro.5560060219

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Citations (162)

The molten globule state of α‐lactalbumin

The FASEB Journal (1996)

Kunihiro Kuwajima

The molten globule stale of a-lactal- bumin Is the best-characterized folding intermediate of globular proteins and has been studied intensively by various spectroscopic and physicochemical techniques, including stopped-flow CD and fluorescence spectroscopies, a hydrogen-exchange technique, 1H- NMR spectroscopy, disulfide-exchange chemistry, site-directed mutagenesis, and calorimetric techniques. This review summarizes recent studies. Major findings about the structure of the molten globule state are: 1) It is highly heterogeneous, having a highly structured a-helical domain with the β-sheet domain being significantly unfolded; and 2) it is not a nonspecific, collapsed polypeptide but already has a native-like tertiary fold. These structural characteristics are essential to fully understand the thermodynamic properties of the molten globule state, which are described in connection with a recently proposed computational approach to predict the structure of the molten globule state of a protein. Mutant proteins in which the stability of the molten globule state was changed were constructed. Studies of the equilibrium unfolding and kinetic refolding of the mutant proteins will provide further insight into the molten globule state as a folding intermediate. In spite of an initial expectation that the structure recognized by an Escherichia coli chaperone, GroEL, is the molten globule, the interaction of GroEL with a-lactalbumin in the molten globule state is much weaker than the interaction with more unfolded states of α-lactalbumin, a disulfide-reduced form, and disulfide rearranged species.—Kuwajima, K. The molten globule state of α-lactalbu- min. FASEB J. 10, 102-109 (1996)

Molten globule

Equilibrium unfolding

Alpha-lactalbumin

Folding (DSP implementation)

10.1096/fasebj.10.1.8566530

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Citations (458)

Rapid formation of a molten globule intermediate in refolding of α-lactalbumin

Folding and Design (1996)

Munehito Arai Kunihiro Kuwajima

Molten globule

Coalescence (physics)

Alpha-lactalbumin

Intermediate state

Folding (DSP implementation)

10.1016/s1359-0278(96)00041-7

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Citations (149)

The Human α-Lactalbumin Molten Globule: Comparison of Structural Preferences at pH 2 and pH 7

Journal of Molecular Biology (2009)

Heike I. Rösner Christina Redfield

Molten globule

Folding (DSP implementation)

Chemical Stability

10.1016/j.jmb.2009.09.025

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Citations (36)

Role of electrostatic repulsion in the acidic molten globule of cytochrome c

Journal of Molecular Biology (1991)

Yuji Goto Shin Nishikiori

Molten globule

Folding (DSP implementation)

Electrostatics

Chemical Stability

10.1016/0022-2836(91)90504-y

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Citations (137)

Curvature Enhances Binding and Aggregation of Huntingtin at Lipid Membranes

Biochemistry (2014)

Maxmore Chaibva Kathleen A. Burke Justin Legleiter

Huntington disease (HD) is a genetic neurodegenerative disease caused by an expanded polyglutamine (polyQ) domain in the first exon of the huntingtin (Htt) protein, facilitating its aggregation. Htt interacts with a variety of membraneous structures within the cell, and the first 17 amino acids (Nt17) of Htt directly flanking the polyQ domain comprise an amphiphathic α-helix (AH) lipid-binding domain. AHs are also known to detect membrane curvature. To determine if Htt exon 1 preferentially binds curved membranes, in situ atomic force microscopy (AFM) studies were performed. Supported lipid bilayers are commonly used as model membranes for AFM studies of protein aggregation. However, these supported bilayers usually lack curvature. By forming a bilayer on top of silica nanobeads (50 ± 10 nm) deposited on a silicon substrate, model supported lipid bilayers with flat and curved regions were developed for AFM studies. The presence of the bilayer over the beads was validated by continual imaging of the formation of the bilayer, height measurements, and spatially resolved mechanical measurements of the resulting bilayer using scanning probe acceleration microscopy. Interpretation of this data was facilitated by numerical simulations of the entire imaging process. The curved supported bilayers associated with the beads were found to be more compliant than flat supported bilayers, consistent with the altered packing density of lipids caused by the induced curvature. This model bilayer system was exposed to a synthetic truncated Htt exon 1 peptide (Nt17Q35P10KK), and this peptide preferentially accumulated on curved membranes, consistent with the ability of AHs to sense membrane curvature.

Membrane Curvature

10.1021/bi401619q

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Citations (57)

Molecular dynamic simulations of oxidized skin lipid bilayer and permeability of reactive oxygen species

Scientific Reports (2019)

Dharmendra Kumar Yadav Surendra Kumar Eun Ha Choi Sandeep Chaudhary Mi‐Hyun Kim

Abstract Lipid peroxidation by reactive oxygen species (ROS) during oxidative stress is non-enzymatic damage that affects the integrity of biological membrane, and alters the fluidity and permeability. We conducted molecular dynamic simulation studies to evaluate the structural properties of the bilayer after lipid peroxidation and to measure the permeability of distinct ROS. The oxidized membrane contains free fatty acid, ceramide, cholesterol, and 5α-hydroperoxycholesterol (5α-CH). The result of unconstrained molecular dynamic simulations revealed that lipid peroxidation causes area-per-lipid of the bilayer to increase and bilayer thickness to decrease. The simulations also revealed that the oxidized group of 5α-CH (-OOH) moves towards the aqueous layer and its backbone tilts causing lateral expansion of the bilayer membrane. These changes are detrimental to structural and functional properties of the membrane. The measured free energy profile for different ROS (H 2 O 2 , HO 2 , HO, and O 2 ) across the peroxidized lipid bilayer showed that the increase in lipid peroxidation resulted in breaching barrier decrease for all species, allowing easy traversal of the membrane. Thus, lipid peroxidation perturbs the membrane barrier and imposes oxidative stress resulting into apoptosis. The collective insights increase the understanding of oxidation stress at the atomic level.

Membrane Lipids

10.1038/s41598-019-40913-y

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Citations (87)