Molecular Structures and Structural Dynamics of Prion Proteins and Prions: Mechanism Underlying the Resistance to Prion Diseases

366 Pages·2015·30.46 MB·English

by  Jiapu Zhang (auth.)

Focus on Structural Biology 9
Jiapu Zhang
Molecular
Structures and
Structural Dynamics
of Prion Proteins
and Prions
Mechanism Underlying the Resistance
to Prion Diseases
Focus on Structural Biology
Volume 9
Serieseditor
RobertKaptein,BijvoetCenterforBiomolecularResearch,UtrechtUniversity,
TheNetherlands
Moreinformationaboutthisseriesathttp://www.springer.com/series/5990
Jiapu Zhang
Molecular Structures and
Structural Dynamics of Prion
Proteins and Prions
Mechanism Underlying the Resistance
to Prion Diseases
123
JiapuZhang
SchoolofSciencesInformation
TechnologyandEngineering
TheFederationUniversity
Ballarat,VIC,Australia
ISSN1571-4853
FocusonStructuralBiology
ISBN978-94-017-7317-1 ISBN978-94-017-7318-8 (eBook)
DOI10.1007/978-94-017-7318-8
LibraryofCongressControlNumber:2015949386
SpringerDordrechtHeidelbergNewYorkLondon
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To myparentsChuantingZhang
andXian’aiLiu

Preface
Studies conducted over the past few decades have demonstrated that rabbits
are immune to prion diseases (also known as transmissible spongiform
encephalopathies(TSEs)).Unlikeconventionalinfectiousdiseases–whichrequire
thatamicroorganismbringDNA,RNAorbothintothebody–priondiseasescan
be causedbythe body’sownproteinsonly(withoutDNA, RNA or both).Mostly,
they attack the brain and other neural tissue and are currently untreatable and
universally fatal. High temperature 120(cid:2)130ıC for 4h still cannot kill diseased
prions. Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker (GSS)
syndrome, fatal familial insomnia (FFI) and kuru are the main prion diseases
affecting humans. The widely known “mad cow” disease (bovine spongiform
encephalopathy(BSE) in cattle), scrapies (“la tremblante” in French language) in
sheep and goats, transmissible mink encephalopathy (TME), feline spongiform
encephalopathy(FSE),chronicwastingdiseases(CWDs) in elksanddeers,exotic
ungulate encephalopathy (EUE), etc. are also diseases of prion nature. These
conditions are degenerative,with death occurring several months to several years
afterinfection.Prioncontainsno nucleicacids, and itis a misshapenproteinthat
acts like an infectious agent. There is no cure and potential treatments are highly
speculative. However, a great deal of effort is being expended to find out why
rabbitsareimmunetopriondiseases.From2005to2012,molecularbiologistshad
already identified the nuclear magnetic resonance (NMR) and X-ray structures of
rabbitprionproteinanditsmutants.Inadditionrabbits,horses,dogsandbuffaloes
are immune to the degenerative conditions too, and by the end of 2013, except
for buffalo their NMR molecular structures were identified too. The author has
simulated how these proteins (including those of humans, mice and elks) change
shape as their temperature and pH change. This book reports the clear change
of rabbit prionprotein structure in highertemperatureand low pH conditionsand
concludesthatsaltbridgesareclearlycontributingtothestructuralstabilityofrabbit
prion protein so that this secret revealed could help in developing a treatment to
priondiseases.PartIofthisbookwilldothemoleculardynamics(MD)simulations
onallthespeciesmentionedabove.
vii
viii Preface
X-ray crystallography is a powerful tool to determine the protein’s three-
dimensional (3D) structure. However, it is time-consuming and expensive, and
not all proteins can be successfully crystallised, particularly membrane proteins.
Although NMR spectroscopy is indeed a very powerful tool in determining 3D
structuresof membraneproteins, it is also time-consumingand costly. Due to the
unstable,noncrystallineandinsolublenatureofsomeproteins,thetechnologiessuch
asX-raycrystallography,NMRspectroscopy,dualpolarisationinterferometry,etc.
cannot produce the 3D structures of these proteins. In this condition, molecular
modelling (MM) might have been the only strategy to get the 3D structures.
Neurodegenerativediseasesareamyloidfibrildiseases.Amyloidfibrilsareunstable,
noncrystallineand insoluble.Thisbookwill also doMM forprionamyloidfibrils
from the point of view of global optimisation (GO) algorithm computations. The
MMworkswillbedoneinPartIIofthisbook.
Thebookisidealforresearchersofnormalprionproteinsanddiseasedprionsas
well as for teachersin biochemistry,biophysics, bioinformatics,material sciences
andengineering,operationsresearch,appliedmathematics,theoreticalphysics,etc.
Acknowledgments: All the MD computational results of this book were cal-
culated on the Tango machines of VPAC (Victorian Partnership for Advanced
Computing,www.vpac.org)andtheTamboandMerrimachinesofVLSCI(Victo-
rianLifeSciencesComputationInitiative,www.vlsci.org.au)ofVictoria,Australia.
IamverygratefultothestaffofVPAC,VLSCI,Melbourne,BallaratandSwinburne
UniversitiesforalltheirgreathelpandsupporttomyprojectsnumberedpBall0004,
pMelb0062andVR0063.Igratefullyacknowledgethehelponmoleculardynamics
skillsfromcolleaguesDrs.TitmussSJandZhangJFandonglobal/localoptimisa-
tion skills from Professor Bagirov AM et al. I wish to thank all those who have
helped me in one way or another. This book systematically united my research
results of recent years but without any research fund support; thus, I am in debt
tomyfamily(especiallytomywifeVanessa)andacknowledgethemdeeply.
Melbourne,Australia JiapuZhang
June2015
Contents
1 BasicKnowledge ........................................................... 1
1.1 ProteinStructuresandFunctions.................................... 1
1.1.1 PrionProteinsandPrions .................................. 3
1.2 ProteinStructuralDynamicsandMolecularDynamics............ 4
1.3 MolecularModeling.................................................. 5
1.3.1 AlgorithmstoMinimizetheTotalPotential
EnergyandtheLennard-JonesPotentialEnergy.......... 6
PartI MolecularDynamicsofPrionProteins
2 TheHomologyStructureandDynamics ................................ 17
2.1 MolecularModeling.................................................. 17
2.2 TheHomologyRabbitPrionProteinat500K...................... 18
2.3 MolecularDynamicsMethodsat300and450K................... 18
2.4 Resultsat450KandDiscussion..................................... 19
2.5 ConcludingRemarks................................................. 22
3 TheNMRStructureandDynamicsoftheWild-TypeandMutants.. 25
3.1 Overview.............................................................. 25
3.2 MaterialsandMethods............................................... 26
3.3 ResultsandDiscussion............................................... 26
3.4 AConcludingRemark ............................................... 28
4 Comparedwith the NMR Structure and Dynamics
ofHumansandMice ....................................................... 29
4.1 Overview.............................................................. 29
4.2 MaterialsandMethodsfor300and450K.......................... 29
4.3 ResultsandDiscussionfor300and450K.......................... 30
4.4 ConcludingRemarksforthe300and450K........................ 36
4.5 MolecularDynamicsat350K....................................... 36
ix