Tài liệu Báo cáo khoa học: Perturbation of membranes by the amyloid b-peptide – a molecular dynamics

Perturbation of membranes by the amyloid b-peptide –

a molecular dynamics study

Justin A. Lemkul and David R. Bevan

Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

Alzheimer’s disease is a neurodegenerative disorder in

which the hallmark symptoms include cognitive decline

and dementia [1]. Characteristic of this disorder is the

formation of extracellular amyloid fibrils, and intra￾cellular deposition of hyperphosphorylated tau [2].

Alzheimer’s disease is considered to affect approxi￾mately five million Americans, and this number is

expected to triple by the year 2050, according to recent

estimates from the Alzheimer’s Association. The num￾ber of Alzheimer’s patients worldwide has recently

been estimated at 20–25 million [3]. With the current

annual health care costs estimated at $100 billion in

the USA alone, the molecular basis for this disease is a

topic of intense scientific research.

According to the ‘amyloid hypothesis’, interactions

between the amyloid b-peptide (Ab) and other cellular

components, especially membranes, are considered to

give rise to the neurotoxicity observed in Alzheimer’s

disease. Ab is derived from the amyloid precursor

protein by sequential proteolytic cleavage by two

membrane-bound proteases, b- and c-secretase [2].

The length of the peptide is variable, ranging from 39

Keywords

Alzheimer’s; amyloid; membrane;

protein–lipid interactions; simulation

Correspondence

D. R. Bevan, Department of Biochemistry,

Virginia Polytechnic Institute and State

University, 201 Fralin Biotechnology Center,

Blacksburg, VA 24061, USA

Fax: +1 540 231 9070

Tel: +1 540 231 5040

E-mail: [email protected]

Website: http://

www.bevanlab.biochem.vt.edu

(Received 19 February 2009, revised 24

March 2009, accepted 26 March 2009)

doi:10.1111/j.1742-4658.2009.07024.x

The etiology of Alzheimer’s disease is considered to be linked to interac￾tions between amyloid b-peptide (Ab) and neural cell membranes. Mem￾brane disruption and increased ion conductance have been observed

in vitro in the presence of Ab, and it is assumed that these same phenom￾ena occur in the brain of an individual afflicted with Alzheimer’s. The

effects of Ab on lipid behavior have been characterized experimentally, but

details are lacking regarding how Ab induces these effects. Simulations of

Ab in a bilayer environment can provide the resolution necessary to

explain how the peptide interacts with the surrounding lipids. In the pres￾ent study, we present an extensive analysis of lipid parameters for a model

dipalmitoylphosphatidylcholine bilayer in the presence of the 40-residue Ab

peptide (Ab40). The simulated systems examine the effects of the insertion

depth of the peptide, temperature, the protonation state of the peptide, and

ionic strength on the features of the lipid bilayer. The results show that

Ab40 is capable of disordering nearby lipids, as well as decreasing bilayer

thickness and area per lipid headgroup. These phenomena arise as a result

of the unfolding process of the peptide, which leads to a disordered,

extended conformation that is capable of extensive electrostatic and hydro￾gen-bonding interactions between the peptide and the lipid headgroups.

Comparisons are made using melittin-dipalmitoylphosphatidylcholine sys￾tems as positive controls of a membrane-disrupting peptide because these

systems have previously been characterized experimentally as well as in

molecular dynamics simulations.

Abbreviations

Ab, amyloid b-peptide; Ab40, 40-residue alloform of the amyloid b-peptide; DMPC, dimyristoylphosphatidylcholine; DPPC,

dipalmitoylphosphatidylcholine; MD, molecular dynamics.

3060 FEBS Journal 276 (2009) 3060–3075 ª 2009 The Authors Journal compilation ª 2009 FEBS